Breast Cancer Extended 645e29
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Breast Cancer Protocols Isolates, Herbs and Formulations
Protects normal cells and tissues against damage caused by chemo or radiotherapy
Prolongs life span and QoL in late stage cancer
Enhances the potency of chemo and radiotherapy
TCM as a Complementary Therapy for Cancer
Improves quality of life, physically and mentally. Allows patients to feel some control
Improves general condition and fatigue, increases body resistance [email protected]
Reduces inflammation and reduces or stops angiogenesis
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MeSH Search & Databases * ("breast neoplasms"[MeSH ] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]) AND herbs[All Fields] This search provided 132 articles * ("breast neoplasms"[MeSH ] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]) AND supplements[All Fields] produced 806 articles * Traditional Chinese Medicine Information Database: http://tcm.cz3.nus.edu.sg/group/tcm-‐id/tcmid_ns.asp. 16/12/14 http://www.megabionet.org/tcmid/
Bio-‐Active • Most modern medicines clinically available for cancer treatments are expensive and known for their toxicity and serious adverse reactions. • It is important to provide scientific evidence for the benefit of bioactive constituents used in ancient systems of medicine and identify novel compounds/ molecules from natural sources 4 (Swaroop et al., 2014).
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CM & Cancer * According to the theory of Chinese medicine (CM), the evaluation of how to treat cancer with CM is a criterion of whether the patient's subjective symptoms are being improved or not, which cannot necessarily be proven by Western medicine (WM). * On the one hand, almost all cancer patients in China would turn to CM treatment; on the other hand, valid evidences in the CM field cannot be offered to convince specialists in the WM field, and the effectiveness of CM cannot be explained either (Yang & Liao, 2010).
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CM & Cancer * Before a uniform curative effect evaluation standard comes out and is accepted, the up-‐to-‐date indices like disease control rate (DCR), time-‐to-‐progression (TTP), Karnofsky performance score (KPS) , body weight, and relevant main symptoms of disease could be used as short-‐term standards. * While indexes of progression-‐free survival (PFS), time-‐to-‐ progression (TTP), disease-‐free survival (DFS), overall survival (OS) could be used as long-‐term standards. Such methods could both represent the advantages of CM, and be accepted by WM (Yang & Liao, 2010).
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Breast Cancer * Every year, among the 1.2 million women diagnosed with breast cancer worldwide, 500 thousand cases die of the disease. Along with a sharp increase in life expectancy, expansion of urbanisation and adaptation of western lifestyle, the increase in incidence rates is even more obvious in developing countries (Hortobagyi et al, 2005; Schulz et al, 2008). * In China, the number of cases increased by 38.5% from 2000 to 2005. Compared with the early surveys in the 1990s, breast cancer ed for the largest increase in mortality rates in 2005 (Yang et al, 2005). * In 2009, breast cancer was the most common cancer in Australian women, ing for 27.4 per cent of all new cancers in women, with the average age of 60.7 years and with the risk of 1 in 8 women 7 16/12/14 before 85 year old
Breast Cancers * Between 65 to 75 per cent of breast cancers are hormone receptor-‐positive. * About 15 to 20 per cent of all breast cancers are HER2+ * About 15-‐20 per cent of all breast cancers in the U.S. are TNBC. * BRCA1 and BRCA2 mutations for about 20 to 25 per cent of hereditary breast cancers and about 5 to 10 per cent of all breast cancers. * 5 per cent are metastatic when discovered * 20% to 30% of patients with early breast cancers will experience relapse with distant metastatic disease [email protected]
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Breast Cancer * There is a 10% to 30% chance of recurrence and metastasis after treatment. Among the patients with local recurrence, 75% to 93% will eventually develop distant metastasis with an extremely low 5-‐year survival rate. * Chinese medicine adopts an overall therapeutic approach to treat and prevent recurrence and metastasis, to improve the immune system of patients, and to strengthen the body’s susceptibility to diseases. Meanwhile, Chinese medicine also aims at reducing the side effects of radiotherapy and chemotherapy, reversing drug resistance and improving quality of life and survival for patients (Mukherjee et al, 2001; Hsiao et al., 2010). [email protected]
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Breast Cancer & TCM * Inspecting the history of drug development during the past half century demonstrates that natural resources represent a significant segment on the pharmaceutical market compared to randomly synthesised compounds. As compiled by the World Health Organization, more than 21,000 plant species have been used worldwide in herbal medicines. * Herbs are an important source for drug development. The traditional Chinese medicine (TCM) has held and still holds an important position in primary health care in China and has been recently recognised by Western countries as a fertile source for revealing novel lead molecules for modern drug discovery (Li-‐Weber 2013). [email protected]
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PubMed database from 1960 to 2013 * Since a tremendous interest in acupuncture and herbal medicine was observed in 2000, the increasing numbers of published papers per year are apparent. In 2013, more than 90 papers on acupuncture and more than 450 papers on herbal medicines appeared in the area of cancer prevention and therapy. Survey of literature deposited in the PubMed database from 1960 to 2013 with the keywords (a) “acupuncture” or “herbal” and (b) “acupuncture and cancer” or “herbal and cancer.” [email protected]
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Cancer * The first mention of cancer was in the Song Dynasty (ca. 1300 AD).The Chinese word Ai (癌) meaning malignant carcinoma – first appeared in the ancient medical book “Wei Ji Bao Shu” (衛 濟寶書). According to the theories of TCM, cancer is caused by imbalances between endogenous physical conditions of the body and exogenous pathogenic factors. * The internal condition of the body plays a dominant role in the onset of cancer. In other words, factors can induce cancer only when the body's own defence system fails. * Those pathogenic factors, in Chinese medicine , include accumulated ‘Toxins’, ‘Heat and Blood Stasis’, and they attack when a person is in a weak physical condition, without the 16/12/14 strength to resist (Hsiao & Liu, 212 010).
TCM & Breast Cancer * Traditional Chinese medicine (TCM) may serve as a useful model for scientific inquiry since there is a standardised system of diagnostics and therapies, and this discipline is practiced worldwide. Among the components of TCM, herbal or botanical agents possess complex biological activities that could affect many aspects of carcinogenesis such as cell growth and proliferation, apoptosis, host-‐tumour interactions, and immune function and differentiation (Hsiao & Liu, 2010). * The theory of TCM coupled with laboratory studies and safety information can serve as a basis for the design of more definitive trials of TCM for specific indications in breast cancer (Cohen et al., 2002). [email protected]
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Patterns in Chinese medicine * A common causative pattern is that excessive ‘Heat’ from a deficient ‘Liver’, combined with ‘Phlegm Dampness’ due to ‘Spleen’ dysfunction, results in the blockage of qi and ‘Blood’, which then "condenses" into breast cancer. * Another common causative pattern is when ‘Liver’ Deficiency and ‘Kidney’ Deficiency lead to qi and ‘Blood’ Deficiency. Chronic qi and ‘Blood’ deficiency then leads to qi ‘Stagnation’ and ‘Blood Stasis’, which causes the formation of lumps in the breast (He et al, 2012).
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Patterns in Chinese medicine * A third pattern is when qi ‘Stagnation’ and ‘Phlegm’ accumulation lead to excessive ‘Heat Toxins’, which then turn to hard breast lump masses. * Traditionally, four patterns of breast cancer are differentiated for treatment: ‘Liver qi Stagnation’ (hard masses without pain and redness); ‘Phlegm Heat Obstruction’ (hard masses with sharp pain and redness and swelling); ‘Liver/Kidney Deficiency’ (hard lumps with swelling and a dimpled appearance of the breast skin, discharges and indentation of the nipple); ‘qi/Blood Deficiency’ (hard lumps with swelling, ruptured abscesses, spreading to the surrounding areas). [email protected]
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Patterns DCIS * Traditional Chinese Medicine (TCM) differential diagnoses for patient with ductal carcinoma in situ (DCIS). * Bars represent the frequency with which various TCM diagnoses were given preceding treatment. There are nine instances of spleen qi deficiency, either alone (seven instances) or as heart blood and spleen qi deficiency (two instances) (Dehen, 2013).
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Breast Cancer & CHM * The reported incidence of use of complementary and alternative medicines (CAMs) among women with breast cancer ranges from 66.7 to 97% (Matthews et al., 2007; Chen et al. 2008) * Traditional Chinese medicine (TCM) has been growing in popularity and has offered an important alternative or complement to health care in many countries. The most common type of CAM used by Chinese women with breast cancer is Chinese herbal medicine. * The majority of patients reported that they had benefited from the use of CHM (Cui et al., 2004).
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Breast Cancer & CHM * Previous studies have disclosed the potential beneficial synergistic effects of the usage of Radix Angelica sinensis (Serafim et al., 2011) or Radix Panax ginseng (Kim et al., 2010) among women with breast cancer. Jia Wei Xiao Yao San (Augmented Rambling Powder) was the most frequently prescribed formula (Lai et al., 2012). * A previous four-‐year survey by Cui et al., (2004) indicated that over 50% of breast cancer patients considered CHP effective in treating cancer.
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Breast Cancer & CHM * Results suggest that, under the coexistence of the conventional medical treatments and TCM, most breast cancer patients consumed herbal therapies with the intention of relieving their treatment-‐induced symptoms, rather than rejecting standard cancer treatments (Lai, Wu, Wang, 2012). * Patients who were younger, married, had higher education or income, received chemotherapy or radiotherapy, or had recurrence/metastasis of cancer tended to use CHM more frequently than other patients.
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Breast Cancer & CHM * From the herbal perspective, breast cancer is the local manifestation of a whole-‐body disease, referred to as an intrinsically deficient but extrinsically excessive syndrome. * Based on TCM theories, deficiency of ‘Spleen qi’, inadequate source of engendering transformation, deficiency of qi and ‘Blood’, and excess of ‘Phlegm-‐Dampness’ are believed to be the main mechanism responsible for development of breast cancer. * The recurrence and metastasis of breast cancer is considered to have a close relationship with ‘Liver dysfunctions’. These prescriptions focus on the herbs for nourishing the ‘yin-‐Blood’, and emolliating and regulating the ‘Liver’. Strengthening of ‘Liver’ function seems to be the key to successful treatment 20 16/12/14 (Chen et al., 2011).
Breast Cancer & the Microenvironment * Many tumours, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. * These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumour microenvironment — including mesenchymal stem cells, adipocytes, tumour associated fibroblasts, endothelial cells, and immune cells — through networks of cytokines and growth factors. * There is now overwhelming evidence that the behaviour of tumourigenic cells is also highly influenced by their microenvironment (Korkaya, Liu, Wicha, 2011). [email protected]
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Elevated levels of cytokines and growth factors produced by tumour cells enhance the proliferation and survival of CSCs, induce angiogenesis, and recruit tumour-‐associated macrophages, neutrophils, and mast cells, which secrete additional growth factors, forming a positive loop that promotes tumour cell invasion and metastasis. Metastatic Tumour
doi:10.1172/JCI57099
Non-‐metastatic Tumour
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Cytokines secreted by cells in the tumour microenvironment regulate BCSC self renewal. Tumour-‐associated fibroblasts (TAFs) and macrophages (TAMs) and MSCs have been shown to secrete IL-‐6, IL-‐8, and CXCL7, which in turn activate Stat3/NF-‐κB signalling, leading to self renewal of BCSCs. This generates a positive loop between the tumour microenvironment and tumor cells. doi:10.1172/JCI57099
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Isolates, Herbs and Formulas
Treatments
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The altered protein molecules upon treatments of TCM h25 erbal medicines and the associated cellular signalling networks. [email protected]
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Network Pharmacology Approach for CHM Research. * For the discovery of CHM-‐derived targets, effect prediction, mechanism clarification, and new drug assistant discovery using network pharmacology approach. It analyzes the information from public data, high-‐throughput experimental data, and TCM data and constructs a “CHM-‐TCM syndrome disease” interaction network using technologies of network expansion, optimisation, comparison, knockout, and addition. Finally, it carries out computational and experimental verifications. 26 16/12/14 doi: 10.1155/2013/621423
Triple Negative Breast Cancer
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TNBC * Triple-‐nega+ve breast cancer (TNBCa) (oestrogen receptor nega+ve, progesterone receptor nega+ve and human epidermal growth factor receptor 2 (Her2) nega+ve s for 10 to 17 per cent of all breast cancers . * They tend to be more aggressive than other types of breast cancer and have poor prognosis. The cause of death of pa+ents with TNBC is oFen recurrence (30-‐40% of cases), which presents as distant metastasis. * Unfortunately, the an+-‐tumour efficacy of commonly used chemotherapeu+c agents for TNBC, including pla+num-‐based chemotherapy, is limited due to acquired drug resistance and toxici+es. [email protected]
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TNBC * Triple negative breast cancer (TNBC) presents clinical challenges due to unknown aetiology, lack of treatment targets, and poor prognosis. Lee et al., (2014) examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. * Results suggest that TNBC was associated with 6 DNA-‐repair non-‐synonymous single nucleotide polymorphisms (nsSNPs); ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and b-‐carotene). [email protected]
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TNBC * Betulinic Acid (BetA), a pentacyclic triterpene discovered in 1995 from the stem bark of the plant Zizyphus mauri-ana, was ini+ally reported to be a melanoma-‐specific cytotoxic agent . Since then, BetA has been found to exhibit a variety of biological and medicinal proper+es such as an+-‐bacterial, an+-‐ malarial, an+-‐inflammatory and an+-‐cancer ac+vi+es * Weber et al (2014) inves+gated the cytotoxic effect of BetA on breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines. Furthermore, the an+-‐inflammatory and an+-‐angiogenic poten+al of BetA was also examined.
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BetA * Possible molecular mechanisms by which BetA induces cell cycle arrest in breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines, BetA treated cells were analysed for their DNA content by propidium iodide staining. * The data suggest that BetA treatment of MDA-‐MB-‐231 cell line could lead to the inhibi+on of DNA synthesis causing the arrest of cells in the G2 phase, eventually restraining the prolifera+on of cells. * The treatment of MDA-‐MB-‐231 cell line with 1 and 10µg/mL BetA lowered the expression of P21, P27, CDK2, CDK6 and Cyclin Dl whereas 20µg/mL BetA lowered the expression of p27 and CDK6 only. BetA treatment of MDA-‐MB-‐231 cell line co-‐cultured with stromal cells lowered the expression of p21, p27 and Cyclin D1. 31
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BetA * BetA proved to be a potent anti-‐inflammatory, anti-‐ proliferative and anti-‐angiogenic agent against breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines. * Given the fact that BetA treatment in vitro has been effective against TNBC, further studies are clearly warranted to determine its effect in vivo. * The effectiveness of BetA shows that it may be highly effective and has great potential in combination with conventional chemotherapeutic regimes therefore possibly enhancing the inhibition of tumour proliferation, inflammation and angiogenesis. [email protected]
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Panaxea Cory)Cur * Cory)Cur consists of Yanhusuo (Rhizoma Corydalis) and Ezhu (Rhizoma Curcumae) and has been an archaic Chinese medicine prescription since Song Dynasty (960-‐1279 AD). Cory)Cur was first recorded in ‘Ji Feng Pu Ji Fang (vol. 20)’ and ‘Zhu Shi Ji Yan Fang (vol. 10)’ in the Song dynasty, and used to improve blood circulation, to remove blood stasis, and to promote circulation for pain relief. * Both yanhusuo and ezhu could inhibit cancer cell proliferation, and ezhu induces cancer cell apoptosis, whereas yanhusuo was shown to inhibit metastasis.
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Panaxea Cory)Cur * Extracted by 95% ethanol, the ratio of 3:2 (ezhu to yanhusuo) results in Cory)Cur having strong synergistic antitumour effects in MDA-‐MB-‐231 cancer cells. * Findings by Gao et al., (2009) propose that the synergy observed in the cytotoxic effects of ezhu and yanhusuo in the human breast cancer cell line, MDA-‐MB-‐231, was caused by suppressing cancer cell proliferation and invasion. The mechanisms should be related with the down-‐regulation of phospho-‐ ERK1/2 and enhancement of the cytochrome c release.
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Corydalis * In another study, Gao et al. (2008) found that the yanhusuo extract inhibited the migration and invasion of MDA-‐MB-‐231 cells in vitro. In addition, the yanhusuo extract inhibited the mRNA expression and activity of MMP-‐9. * The anti-‐cancer metastasis effect of yanhusuo involved the activation of p38 and inhibition of ERK1/2 and SAPK/JNK mitogen-‐activated protein kinase (MAPK) signalling. * Nine alkaloids from the dichloromethane extract of C. yanhusuo and were tested for their aromatase binding activities. The results showed that the quaternary protoberberine alkaloids and the tertiary protoberberine alkaloids had aromatase binding activities (Shi et al., 2010) [email protected]
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Ganoderma lucidum * Ganoderma lucidum (ling zhi) suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-‐kappaB activity in MDA-‐ MB-‐231 cells. * The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-‐kappaB-‐ regulated cyclin D1, followed by the inhibition of cdk4. * Ganoderma lucidum suppresses the invasive behaviour of breast cancer by inhibiting the growth of MDA-‐MB-‐231 breast cancer (Jiang et al., 2004). [email protected]
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Strobilanthes crispus * Selected sub-‐fractions of the dichloromethane extract of S. crispus induced death of MCF-‐7 (breast), MDA-‐MB-‐231 (TNBC), PC-‐3 (prostate) and DU-‐145 (prostate) cells (Yaacob et al., 2010). * The combined Strobilanthes crispus leaves (SCS) and tamoxifen treatment displayed strong synergistic inhibition of MCF-‐7 and MDA-‐MB-‐231 cell growth at low doses of the anti-‐oestrogen. SCS further promoted the tamoxifen-‐induced apoptosis that was associated with modulation of mitochondrial membrane potential and activation of caspase-‐8 and caspase-‐9, suggesting the involvement of intrinsic and extrinsic signalling pathways (Yaacob et al., 2014). [email protected]
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Shiraia bambusicola * 11,11'-‐dideoxy-‐verticillin, a compound of the novel epidithiodioxopiprazine structural class, is isolated from the traditional Chinese medicinal herb Shiraia bambusicola (zhu huang) and has potent tyrosine kinase-‐inhibitory and anti-‐ tumour activities. * 11,11'-‐dideoxy-‐verticillin significantly inhibited the activities of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-‐1/fms-‐like tyrosine kinase-‐1 (VEGFR-‐1/ Flt-‐1) and human epidermal growth factor receptor-‐2 (HER2/ ErbB-‐2), with relative specificity on EGFR and VEGFR-‐1. MB-‐ MB-‐468 cells exhibited significant apoptotic morphological changes (Zhang et al., 2005). [email protected]
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TNBC * 50 cases of postoperative TNBC were given JLBSHJ formula orally, the control group consisting 50 cases took chemotherapy. 5-‐year observation was followed. * The survival rate was in the control group 80%, the treated group 94%; the life quality improving rate: the control group 68%, the treated group 90%; local recurrence rate: the control group 36%, the treated group 20%, remote metastasis rate: the control group 24%, the treated group 6%. * Total recurrence rate: the control group 76%, treated group 26%; bone marrow inhibition rate: the control group 90%, the treated group 10% [email protected]
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TNBC * Cellular immune function: CD4/CD8 ratio in the control group was (1.10±0.18), and the treated group was (1.47±0.30) (P<0.05); NK cell activity in the control group was (19.13±4.86), and(30.16±6.06) in the treated group (P<0.05). * Compared with chemotherapy regimen, the treatment of JLBSHJ on postoperative TNBC could prolong the survival rate of the patients, improve their life quality, increase cellular immune function, lower side and toxic effect, and lower remote metastasis rate (Hu Bei Zhong Yi Za Zhi. 2010, 32(6): 16-‐17)
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Ji Li Bu Shen He Ji Formula * Semen Astragali complanati (sha yuan zi or tong ji li) 30g * Radix Rehmanniae Glutinosae Praeparata (shu di) 20g * Radix Dioscoreae Oppositae (shan yao) 15g * Fructus Corni Officinalis (shan zhu yu) 10g
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* Fructus Lycii (gou qi) 15g * Radix Glycyrrhizae Uralensis Praeparata (zhi gan cao) 6g * Cortex Eucommiae Ulmoidis (du zhong) 15g * Cortex Cinnamomi Cassiae (rou gui) 3g * Radix Aconiti Carmichaeli Praeparata (fu zi) 15g
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TNBC * 40 cases of TNBC were averagely divided into 2 groups according to the patients’ choice, the treated group was given oral istration of herbs and had regular examination, the control group only had regular examination. * After a few years of clinical research, it’s found that TCM had positive therapeutic effect on TNBC, there’s significant difference compared with the control group. * TCM treatment on TNBC effectively controlled the recurrence and metastasis of these patients, prolonged the survival time and improved the life quality (Zhong Guo wu Zhen Xue Za Zhi. 2010, 10(19): 4566-‐4567). [email protected]
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Formula 2 * Rhizoma Iphigeniae Indicae (shan ci gu) 30g * Herba Solanum Nigrum (long kui) 30g * Radix Bupleuri (chai hu) 15g * Tuber Curcumae (yu jin) 15g * Rhizoma Sparganii Stoloniferi (san leng) 15g * Rhizoma Curcumae Ezhu (e zhu) 15g [email protected]
* Rhizoma Pinelliae Ternatae (ban xia) 12g * Spica Prunellae Vulgaris (xia ku cao) 15g * Concha Ostreae (mu li) 30g * Radix Glycyrrhizae Uralensis (gan cao) 10g * Radix Angelicae Sinensis (dang gui) 15g
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Oestrogen Receptor / Progesterone Receptor Positive
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Oestrogen Metabolism * The liver is a site for biosynthesis of oestrogens but it is also the main site for further biotransformation of them. Once the oestrogens are synthesised by aromatase in peripheral tissues including the liver, they will be released to the circulation. * Oestrone is in equilibrium with oestradiol and 17-‐b-‐ hydroxysteroid dehydrogenase (17bHSD) in this respect. The oestrogens are taken up by the liver where they will be bio-‐ transformed further in to different metabolites. The major oxidative routes of oestrone and oestradiol are 2-‐ and 4-‐ hydroxylation by cytochrome P450 (CYP) 2B1, 1A and 3A. Other minor oxidative pathways are also identified. [email protected]
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Oestrogen Metabolism * Oxidative metabolism of the oestrogens oestrone (E1) and oestradiol (E2) is the critical event in the initiation of cancer by oestrogens. E1 and E2 are oxidised by cytochrome P450 (CYP) to the catechol oestrogens 2-‐OHE1(E2) and 4-‐OHE1(E2) and then to the catechol oestrogen quinones, which react with DNA to form oestrogen-‐DNA adducts. * Oestrogen metabolism becomes unbalanced when expression of the activating enzymes CYP19 (aromatase) and CYP1B1 is higher and expression of the protective enzymes catechol-‐O-‐methyltransferase and quinone reductase is lower (Rogan & Cavalieri, 2011). [email protected]
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Oestrogen Metabolism * The 2-‐ and 4-‐hydroxy derivatives (and other metabolites) will be further converted to 2-‐ and 4-‐methoxy metabolites by catechol-‐O-‐methyltransferase (COMT). While the hydroxylated metabolites appear to result in DNA damage and contribute to the tumorigenic effect of oestrogen, the methoxy-‐derivatives appear to exhibit beneficial cardiovascular effects. * Oestrone and oestradiol and their metabolites undergo sulfation by sulfotransferases (SULTs) and glucuronidation by glucoronyltransferases (UGTs). Oestrone and oestradiol sulfates could be deconjugated by sulfatases (STs). [email protected]
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Oestrogen Metabolites * 16 alpha-‐OHE1 is a powerful metabolite that stimulates target tissues. Levels can rise in response to obesity, alcohol consumption, and toxic exposure. High levels of this potent metabolite are linked to increased risk and poorer prognosis in conditions linked to oestrogen excess such as breast cancer and lupus. * 4-‐hydroxyestrone (4-‐OHE1) – may react negatively with damaged DNA. It plays an important role in breast carcinogenesis because of its ability to induce DNA depurination independent of ER binding. 4OHE1 concentration, may have confounded results for oestrogen metabolite ratio (EMR). 48
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Metabolic Pathways * The two main pathways for metabolising oestrogen are via 16alpha-‐hydroxylation and 2-‐hydroxylation. The 16α-‐OHE1 metabolites are biologically active; the 2-‐OHE1 metabolites are not. It is suggested that women who metabolise a larger proportion of their endogenous oestrogen via the 16alpha-‐ hydroxy pathway may be at significantly elevated risk of breast cancer compared with women who metabolise proportionally more oestrogen via the 2-‐hydroxy pathway. * Studies by Ursin et al., (1997) and Cauley et al., (2003) do not the hypothesis that the ratio of the two hydroxylation metabolites (2-‐OHE1/16alpha-‐OHE1) is an important risk factor for breast cancer [email protected]
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Metabolic Pathways * There are indications that additional factors such as certain genetic polymorphisms and excessive oxidative stress are necessary to influence the synthesis of intermediate aggressive metabolites, which may already have gene toxicity at low concentrations and can destruct DNA structures and/ or have the potency to influence carcinogenesis by intensive proliferative actions (Mueck & Seeger, 2007). * It remains doubtful whether physiological oestradiol per se can be causally carcinogenic by proliferative processes (International Menopause Society, 2009).
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Oestrogen Metabolism Progesterone DHEA-‐S
Androstenedione
SHBG
Testosterone Oestrone Sulphate
Oestrodiol (E2) Oestrone (E1)
2-‐OHE1
4-‐OHE1
16α-‐OHE1
2-‐MeOE2
4-‐MeOE2
Oestriol (E3)
Carcinogenic metabolites are shown in red and anti-‐carcinogenic or neutral metabolites are shown in green.
Genes Evaluated by EstroGene Test * Phase I Detoxification * CYP1A1 * CYP1B1 * CYP3A4
Oestrone to 2-‐OH Oestrone (E1) Oestrone to 4-‐OH E1 Oestrone to 16-‐alpha OH E1
* Phase II Detoxification * COMT Methylation of 2-‐OH and 4-‐OH E1 * GST Quinones to Glutathione Conjugates * MnSOD Free Radicals Quenced https://www.estrogengenetest.com/ Enter: MPI license number for Practitioner discount
Botanicals & Oestrogen Metabolism * Panax notoginseng significantly increased mRNA expressions of GSTm1 and CYP1A1 in the 2 g·∙kg-‐1 and 4 g·∙kg-‐1 bw/d treatment groups, respectively, but P. notoginseng had a inhibitory tendency on mRNA expressions of CYP1B1 and significantly inhibited the expressions of CYP2B1 (Yang et al., 2009). * Rhizoma curcumae extract could increase and induce the enzyme activity and mRNA expression of CYP3A4 (Shao et al., 2008). * Flos Chrysanthemi, Fructus Lycii, Radix et Rhizoma Salviae Miltiorrhizae, Fructus Crataegi, Flos Lonicerae Japonicae, Rhizoma Dioscoreae are inducers of CYP3A4 (Xu et al., 2011). [email protected]
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Who Should be Tested to Reduce Breast Cancer Risk? * Women’s Health Initiative study first published in 2002 conclusively demonstrated the 2.5 increased breast cancer risk from cumulative oestrogen exposure. How can we pinpoint which women are more at risk? * By a genetic assessment of how a woman metabolizes oestrogen. Women with 3 or more genetic mutations have 2.5 to 13x greater breast cancer risk. All women should be tested to know if they possess the risk * Practically speaking, testing should take place when contemplating exogenous oestrogen use or for those with ER+ breast cancer history
Oral Contraceptives
In Vitro Fertilization
Hormone Replacement Therapy
Bio-‐identical Hormones
ER-‐Positive Breast Cancer
ER-‐Positive Breast Cancer Family History
Testing * It is appropriate to test every woman once in their lifetime, perhaps as part of an initial gynecological screening. Practically speaking, the Oestrogen Gene Tests should be ordered when before prescribing exogenous oestrogens. For example, prior to starting oral contraception, hormone replacement therapy or bio-‐identical hormones, and especially IVF. All women with current or previous exposure should be tested. * Certainly, women with a history of oestrogen receptor-‐ positive breast cancer need to know or that they have multiple snps and add oestrogen metabolism improvement techniques to their standard breast cancer treatment. [email protected]
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Erα vs ERβ * The oestrogen receptor (ER) isoform known as ERβ has become the focus of intense investigation as a potential drug target. The existence of clear-‐cut differences in ERβ and ERα expression suggests that tissues could be differentially targeted with ligands selective for either isoform (Couse et al., 1997; Enmark et al., 1997). * In particular, the fact that ER β is widely expressed but not the primary oestrogen receptor in, for example, the uterus (Harris, Katzenellenbogen, & Katzenellenbogen, 2002) opens up the possibility of targeting other tissues while avoiding certain classical oestrogenic effects. [email protected]
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Daidzein * Charalambous, Pitta & Constantinou (2013) found that equol (>50 μM) and 4-‐hydroxy-‐tamoxifen (4-‐OHT; >100 nM) both significantly reduced the breast cancer MCF-‐7 cell viability. Daidzein and its metabolite S-‐(-‐)-‐equol showed the potential of inhibiting the growth of mammary tumours. Daidzein or S-‐ (-‐)-‐equol could be used as a core structure to design new drugs for breast cancer therapy. Our results indicate that consumption of daidzein may protect against breast cancer (Liu et al., 2012). * Daidzein could induce breast cancer cell apoptosis through the mitochondrial caspase-‐dependent cell death pathway (Jin et al., 2010). [email protected]
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S-‐Equol * The soy isoflavone daidzin was isolated and shown to be a precursor to equol (Axelson et al., 1982). It was also found that the introduction of soy protein to the diet led to an increased excretion of equol in some but not all adults (Setchell et al., 1984). * The finding of high concentrations of equol, a nonsteroidal oestrogen; in the urine of adults consuming fermented soy foods prompted the hypothesis that this nonsteroidal oestrogen may be beneficial in the prevention and treatment of many hormone-‐dependent conditions.
[email protected]
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Erα vs ERβ * Isoflavone (genistein) consumption indicate the possible contribution of ERβ-‐specific signalling in breast cancer prevention. A selective oestrogen receptor modulator, which works as an antagonist of ERα and an agonist of ERβ, may be a promising chemo-‐preventive treatment (Saji, Hirose, & Toi, 2005). * ERβ works as counter partner of ERα through inhibition of the transactivating function of ERα by heterodimerization, distinct regulation on several specific promoters by ERα or ERβ, and ERβ-‐specific regulated genes which are probably related to its anti-‐proliferative properties [email protected]
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Genistein * Genistein significantly decreased both gene and protein expression of Rho GTPases (Rho, Rac, and Cdc42) and the downstream effector of Rac and Cdc42, PAK1, are significant for understanding the mechanism by which genistein inhibits cancer cell invasion, and may reduce breast cancer progression via transcriptional regulation (Vadlamudi et al., 2004; Vega & Ridley, 2008). * Genistein is a potent inhibitor of the growth of the human breast carcinoma cell lines, MDA-‐468 (oestrogen receptor negative), and MCF-‐7 and MCF-‐7-‐D-‐40 (oestrogen receptor positive). The presence of the oestrogen receptor is not required for the isoflavones to inhibit tumour cell growth 60 16/12/14 (Peterson & Barnes, 1991)
Genistein * Results also suggest that genistein could be useful as a chemotherapeutic agent in premenopausal women with breast cancer of the ERα-‐negative and ERβ-‐positive type (Rajah et al., 2009). * ERβ has been postulated to play a role in modulating ERα-‐ mediated cell proliferation, genistein and quercetin may be agonists for both receptor types and the ratio of ERα to ERβ is known to vary between tissues and results point at the importance of the cellular ERα/ERβ ratio for the ultimate effect of phytoestrogens on cell proliferation (Sotoca et al., 2008). [email protected]
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See * Daniel Weber. Phytoestrogens and Cancer. Cancer Strategies Journal Winter 2014
[email protected]
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Erα vs ERβ * Selective ER agonists can stimulate either ER-‐α or ER-‐β and induce tissue-‐specific oestrogen-‐like effects. MF-‐101 is derived from 22 herbs that are traditionally used in Chinese medicine for the treatment of menopausal symptoms. * Studies with the MF-‐101-‐isolated active compounds, liquiritigen and chalcone, demonstrated selectivity for ER-‐β, with no induction of proliferative events. MF-‐101 did not promote the growth of breast cancer cells or stimulate uterine tissue (Stovall & Pinkerton, 2009). * MF101, a selective oestrogen receptor β agonist is a safe and effective for treating menopausal hormone therapy and nighttime awakenings (Leitman & Christians, 2012). [email protected]
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MF101 * Scutellaria barbata (Ban Zhi Lian) * Atractylodes macrocephala (Bai Zhu) * Rheum palmatum (Da Huang) * Wolfiporia extensa (Fu Ling) * Triticum aestivum (Fu Xiao Mai) * Glycyrrhiza uralensis (Gan Cao)
* Pueraria montana (Ge Gen) * Glycine max (Hei Dou) * Achyranthes bidentata (Huai Niu Xi) * Huang Qi (Astragalus mongholicus) * Lian Zi Xin (Nelumbo nucifera) * Paeonia suffruticosa (Mu Dan Pi)
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MF101 * Mu Li (Crassostrea gigas) * Nu Zhen Zi (Ligustrum lucidum) * Sheng Di Huang (Rehmannia glutinosa) * Shan Dou Gen (Sophora tonkinensis) * Shan Zhu Yu (Cornus officinalis) * Suan Zao Ren (Ziziphus jujuba)
* Tian Men Dong (Asparagus cochinchinensis) * Epimedium spp. (Yin Yang Huo) * Anemarrhena asphodeloides (Zhi Mu) * Ze Xie (Alisma plantago-‐ aquatica) * Chalcone * Liquiritigenin
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Chalcone * Hsu et al., (2006) examined (1,3-‐diphenyl-‐2-‐propenone) for its effect on proliferation in human breast cancer cell lines, MCF-‐7 and MDA-‐MB-‐231. The results showed that chalcone inhibited the proliferation of MCF-‐7 and MDA-‐MB-‐231 by inducing apoptosis and blocking cell cycle progression in the G2/M phase. * Chalcone extracted from Taraxacum officinale also triggered the mitochondrial apoptotic signalling by increasing the amount of Bax and Bak and reducing the level of Bcl-‐2 and Bcl-‐XL, and subsequently activated caspase-‐9 in MCF-‐7 and MDA-‐MB-‐231 cells. [email protected]
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Liquiritigenin (LQ) * LQ separated from Glycyrrhiza radix, possesses anti-‐ inflammatory, anti-‐hyperlipidaemic, and anti-‐allergic effects. The expression of cleaved PARP, the hall-‐marker of apoptosis, was enhanced by LQ. LQ treatment also resulted in a reduction of the expressions of B-‐cell lymphoma 2 (Bcl-‐2) and B-‐cell lymphoma-‐extra large (Bcl-‐xL), and an increase of the phosphorylation of c-‐Jun N-‐terminal kinases (JNK) and P38. * LQ suppressed the activation of extracellular signalling-‐ regulated kinase (ERKs) and reduced the translocation of phosphor-‐ERKs from cytoplasm to nucleus (Wang et al, 2014). [email protected]
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ER+/PR+ * Ganoderma lucidum and Scutellaria baicalensis, have been reported to suppress ER expression in vitro (Jiang, Slivova & Sliva, 2006; Chung et al., 2008). * Cryptotanshinone has been recently evaluated for its anti-‐ cancer activity and is a potent stimulator of ER stress, leading to apoptosis in many cancer cell lines including MCF7 breast carcinoma. * Cryptotanshinone also evidenced sensitising effects to a broad range of anti-‐cancer agents including Fas/Apo-‐1, TNF-‐α, cisplatin, etoposide or 5-‐FU through inducing ER stress, highlighting the therapeutic potential in the treatment of breast cancer (Park et al., 2012). [email protected]
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ER+/PR+ * Tanshinone IIA is a widely used Chinese herbal medicine isolated from Danshen (Salvia miltiorrhiza) that may have anti-‐ inflammatory and anti-‐oxidant properties, as well as cytotoxic activities against multiple human cancer cell lines. * Tanshinone IIA might have potential anti-‐cancer activity that is stronger than tamoxifen in both ER-‐positive and ER-‐negative breast cancers. This function could be attributed in part to its inhibition of proliferation and apoptosis induction in cancer cells via the downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis and DNA synthesis (Lu et al., 2009). [email protected]
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Panaxea Tanshins * Salvia Miltiorrhiza (contains standardised extracts Tanshinone IIA and Cryptotanshinone) * Cytotoxic * Apoptoxic * Inhibits angiogenesis
[email protected]
* Clears Heat and eliminates toxins, activates blood circulation, dispels stasis, generates body fluids, dispels wind and opens channels and collaterals.
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ER+/PR+ * DNA microarray technology has been used to understand the molecular mechanism underlying the anti-‐cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-‐positive MCF-‐7 and ER-‐negative MDA-‐MB-‐231 cells; specifically, whether it affects the expression of cancer-‐related genes. * Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose-‐ and time-‐dependent manner. The growth-‐inhibitory effect was much more profound in MCF-‐7 cell line than that in MDA-‐MB-‐231 cells (Kang et al., 2005). [email protected]
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Metalloestrogens * Aluminium chloride or aluminium chlorhydrate can interfere with the function of oestrogen receptors of MCF7 human breast cancer cells both in of ligand binding and in of oestrogen-‐regulated reporter gene expression. * This adds aluminium to the increasing list of metals capable of interfering with oestrogen action and termed metalloestrogens (Darbre, 2005). * Other metalloestrogens are arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin (Byrne et al., 2013). [email protected]
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Emodin & Aloe-‐emodin * Huang et al., (2013) reported results that indicated both emodin and aloe-‐emodin are capable of inhibiting breast cancer cell proliferation by down-‐regulating ER α protein levels, thereby suppressing ER α transcriptional activation. Furthermore, aloe-‐emodin treatment led to the dissociation of heat shock protein 90 (HSP90) and ER α and increased ER α ubiquitination. * Data demonstrate that emodin and aloe-‐emodin specifically suppress breast cancer cell proliferation by targeting ER α protein stability through distinct mechanisms.
[email protected]
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Emodin & Aloe-‐emodin * Huang, Chen, Shi (2008) focused on the effect of emodin in human breast cancer BCap-‐37 cells and further understand the underlying molecular mechanism in treating breast cancer. * The results of the study further showed that Bcl-‐2 level decreased, while Bax and cytosolic cytochrome c levels in sample cells increased after the emodin treatment. The decline in the Bcl-‐2/Bax ratio and the increase of cytosolic cytochrome c concentration were consistent with the increase of the apoptotic ratio.
[email protected]
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Panaxea Emodin * Recent research has suggested * Panaxea Emodin Complex that plant polyphenols such as extracted from Rheum Palmatum (da huang) contains emodin may be used to sensitise tumour cells to Emodin (1, 3, 8 -‐ trihydroxy -‐ 6 chemotherapeutic agents and – methylanthraquinone) and radiation therapy by inhibiting Glycyrrhiza Uralensis extract pathways that lead to (gan cao) treatment resistance. Such agents have also been found to be protective from therapy-‐ associated toxicities (Garg et al., 2005) [email protected]
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Panaxea D:Fend * 350mg Daidzein/Daidzin * 470 mg Genistein/Genistin * 110 mg Glycitein/Glycitin Taken with * MicrSoy-‐20 (MS-‐20) or * Haelan 951 (Bachg & Haselhorst, 2007) Or * FSP [email protected]
* MS-‐20 demonstrated its ability to restore chemotherapy-‐ induced immunosuppression and improve quality of life (Chi et al., 2014). * Fermented soy product (FSP) was most efficient in tumour containment, possibly due to a positive modulation of the immune system (Kinouchi et al., 2012) 76
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FSP * FSP caused apoptotic cell death in MCF-‐7 cells. FSP induced generation of reactive oxygen species (ROS) indicating that the ROS production probably was the cause of this apoptotic cell death. This study suggests that FSP retards tumour growth in vivo and can trigger apoptosis in vitro (Chang et al., 2002). * Daily ingestion of the probiotic soy product may contribute to a beneficial balance of the faecal microbiota and this modulation is associated with an improved cholesterol profile (Cavallini et al., 2011).
[email protected]
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Haelan * Haelan helps repair DNA damage, thereby allowing chemotherapy to be more effective. * Haelan is anti-‐angiogenic, and pro-‐apoptotic. * Haelan may disrupt signals of epidermal Growth Factor Receptors; possibly blocking the signals altogether. * Haelan may cause a reactivation of the P53 tumour suppressor protein for these specific patients * Haelan is known to shut off the Nuclear Factor Kappa Beta (NF-‐Kb) mutation capability completely.
[email protected]
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D:FEND * D:FEND normalises cell function and contains herbal phytoestrogens. Phytoestrogens are plant-‐derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits is frequently attributed to phytoestrogens. D:Fend induces apoptosis via the mitochondrial pathway (Stark & Madar, 2002). * It is involved in cell cycle arrest, antiangiogenic potential, antimetastatic potential and in enhancing radiotherapy treatment. In various cancer models phytoestrogens significantly inhibit tumour growth, invasion and metastasis (Virk-‐Baker et al., 2010; Vitale et al., 2013) [email protected]
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Oldenlandia diffusa (OD) * Gu et al., (2012) observed that extracts bai hua she she cao strongly inhibited anchorage-‐dependent and -‐independent cell growth and induced apoptosis in oestrogen receptor alpha (ERα)-‐positive breast cancer cells, whereas proliferation and apoptotic responses of MCF-‐10A normal breast epithelial cells were unaffected. * Mechanistically, OD extracts enhance the tumour suppressor p53 expression as a result of an increased binding of ERα/Sp1 complex to the p53 promoter region. * OD exerts antiproliferative and apoptotic effects selectively in ERα-‐positive breast cancer cells. [email protected]
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Resveratrol & Ursolic Acid * Resveratrol, a phytoalexin, and ursolic acid, a pentacyclic triterpenoid, are two bioactive compounds that have anti-‐ inflammatory actions, induce apoptosis and have anti-‐cancer activities by targeting signal pathways. * Ursolic acid treatments of MCF-‐7 breast cancer cells induced apoptosis through internal mitochondrial pathways (Kassi et al., 2009). This finding is further substantiated when on treating MDA-‐MB-‐231 cells with ursolic acid an induction of mitochondrial mediated cancer cell apoptosis was observed (Kim et al., 2011). Ursolic acid was found to release cytochrome C from the mitochondria to the cytosol, to up-‐ regulate the Bax protein as well as a down-‐regulate Bcl-‐2. [email protected]
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Ursolic Acid * UA was found to inhibit the proliferation of MCF-‐7 cells in a concentration and time-‐dependent manner. After treatment, UA-‐induced apoptosis was accompanied by a significant decrease in CyclinD1/CDK4 expression, which can be regulated by FoxM1. Previous studies demonstrated that FoxM1 orchestrates the transcription of genes that are essential for cell cycle progression and cell proliferation (Wang, Ren, Xi, 2012). * UA-‐induced apoptosis (53 μM), the PARP cleavage, and decreased Bcl-‐2 protein (53 μM) to the notion that UA induces apoptosis through the intrinsic mitochondrial pathway (Kassi et al., 2009). [email protected]
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Panaxea Ursolic Acid * We use only pharmaceutical grade UA that is micronised for greater bio-‐availability. Most UA that is commercially available is either industrial or cosmetic grade.
[email protected]
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Panaxea antiEST * The actions of unopposed oestrogen or oestrogen in the face of progesterone (P) resistance can promote various gynaecologic disorders, including endometriosis, endometrial hyperplasia, and cancer. * Collins et al., (2009) investigated the botanical herb Prunella vulgaris (PV) and found that extracts of this plant have anti-‐ oestrogenic activities. * Methanol extract of PV exhibits significant anti-‐oestrogenic properties, both in vitro and in vivo. This activity is likely due to the ability of PV-‐activated aryl hydrocarbon receptor (AHR) to interfere with oestrogen [email protected]
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HER2/neu
[email protected]
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HER-‐2/neu * HER2 is a member of the epidermal growth factor receptor (EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. * In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. * It is strongly associated with increased disease recurrence and a poor prognosis. Over-‐expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma. [email protected]
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HER-‐2/neu * The amplification and overexpression of the HER-‐2/neu proto-‐ oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumours from human breast cancer patients and are correlated with poor prognosis. * Results indicate that emodin inhibits HER-‐2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-‐2/neu-‐overexpressing cancer cells (Zhang et al., 1995; Zhang et al., 1999).
[email protected]
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P53 & Ki67 * The Ki67 marker and P53 protein are important factors in the HER-‐2/neu breast cancer patients with emphasis on therapeutic agents. Results of the study suggested that the p53 protein and Ki67 marker are important factors in the prognosis of metastasis and survival rate in patients with breast cancer. * It is important that patients of Immunohistochemistry (IHC 2+) with Ki67 positive or p53 positive get treated with adjuvant therapy (Payandeh et al., 2014).
[email protected]
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P53 & Ki67 * Scutellaria baicalensis increased expression of p53 in the cancer cells of key proteins related to the enhancement of apoptosis is observed (Gao et al., 2011). Similarly, Gleditsia sinensis thorns are used as a medicinal herb, which shows a decrease in cell growth and an increase in cell cycle arrest during the G2/M-‐ phase. The arrest is correlated with increased p53 levels and down-‐regulation of cyclinB1 (Lee et al., 2010). * Ki-‐67, a nuclear antigen, is widely considered as a marker of cellular proliferation. With Radix Sophorae Tonkinesis and Rhizoma Curcumae expression of Ki-‐67 antigen was significantly different in the normal, hyperplastic and mild dysplastic cancers (Zhou & Zhang, 2005). 89
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HER-‐2/neu * After surgery selected HER2/neu transgenic spontaneous breast tumour model mice were randomly divided them into control group, traditional Chinese medicine group (RSR group), western medicine group (Trastuzumab group), and the combination group (RSR and Trastuzumab group) and treated with corresponding medicine for 4 month. * “Ru’ai Shuhou Recipe” can inhibit recurrent tumour volume in transgenic mice after operation, block the HER2-‐mediated p38 MAPK and PI3K-‐Akt signal pathways, inhibit tumour cell proliferation and promote tumour cell apoptosis (Shao et al., 2013). [email protected]
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Ru Ai Shu Hou Fang * Rhizoma Alocasiae Macrorrhizae (she liu gu) (decocted first) 60g * Radix Astragali (huang qi) 30gm * Radix Codonopsis (dang shen) 12gm * Radix Atractylodes (bai zhu) 10gm * Herba Epimedii (yin yang huo) 15gm [email protected]
* Radix Adenophorae (nan sha shen) 15g * Rhizoma Curcumae Ezhu (e zhu) 30gm * Herba Salviae Chinensis (shi jian chuan) 30gm * Radix Ledebouriellae Divaricatae (feng fang) 12gm * Cornu Cervi gel (lu jiao pian) 12gm 91
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Ru Ai Shu Hou Fang * Herba Sargassii (hai zao) 30gm * Herba Cistanches (rou cong rong) 12gm * Radix Achyranthis Bidentatae (huai niu xi) 30gm * Fructus Psoraleae Corylifoliae (bu gu zhi) 30gm * Concha Ostreae calcined (duan mu li) 30gm * Rhizoma Curcumae Longae (jiang huang) 30gm 92 * Poria Cocos (fu ling) 12gm
* Os Draconis calcined (duan long gu) 30gm * Radix Cynanchi Paniculati (xu chang qing) 30gm * Gummi Olibanum (ru xiang) 10gm * Herba Scutellariae Barbatae (ban zhi lian) 30gm * Rhizoma Corydalis (yan hu suo) 30gm * Scolopendra Subspinipes (wu gong) 3gm 16/12/14
HER-‐2/neu * Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. * Inhibition of HER-‐2 signalling by specific human epidermal growth receptor 1/HER-‐2 (EGFR/HER-‐2) kinase inhibitor lapatinib synergistically enhanced the anti-‐cancer effects of honokiol in HER-‐2 over-‐expressed breast cancer cells (Liu et al., 2008) [email protected]
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HER-‐2/neu * The anthocyanins cyanidin-3-glucoside (C3G) and peonidin-3-glucoside from Hibiscus sabdariffa have been identified as potential drugs for the therapy of HER2-positive breast cancer. They have been used as supplements in targeted therapeutics and chemotherapeutics in Asia. * The combination treatments induced apoptosis, inhibited cell growth and affected HER2 and its downstream signalling pathway in MDA-MB-453, BT474 and HCC1569 cells, the effects were synergistic. The combination of 3CG and trastuzumab (Trast) inhibited tumour growth in an in vivo xenograft model. The data from the present study suggested that C3G exhibits potent antitumour activity when combined with Trast (Liu et al., 94 16/12/14 2014)
HER-‐2/neu * Tyrosine kinase inhibitors such as emodin can target the HER2/ neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-‐overexpressing breast cancer cells. * Emodin also sensitises HER2/neu-‐overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene (Wang et al., 2001).
[email protected]
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HER-‐2/neu * The combination of emodin AMAD treatment and siRNA against Her2 synergistically inhibited proliferation and induced apoptosis. Taken together, these data suggest that blockade of Her2/neu binding to Hsp90 and following proteasomal degradation of Her2/neu were involved in emodin azide methyl anthraquinone derivative (AMAD)-‐induced apoptosis in Her2/ neu-‐overexpressing cancer cells (Yan et al., 2011).
[email protected]
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HER-‐2/neu * As an anti-‐cancer agent, emodin has been shown to suppress the growth of various tumour cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal, leukaemia, and lung cancers. * Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-‐κB, casein kinase II, HER2/neu, HIF-‐1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer.
[email protected]
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HER-‐2/neu * Apigenin exhibited potent growth-‐inhibitory activity in HER2/ neu-‐overexpressing breast cancer cells. Apigenin-‐induced cellular effects result from loss of HER2/neu and HER3 expression with subsequent inactivation of PI3K and autologous tumour killing (ATK) pathways in cells that are dependent on this pathway for cell proliferation. * This implies that the inhibition of the HER2/HER3 heterodimer function provided an especially effective strategy for blocking the HER2/neu-‐mediated transformation of breast cancer cells. * The degradation of mature HER2/neu involves polyubiquitination of HER2/neu and subsequent hydrolysis by the proteasome (Way et al., 2005). [email protected]
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HER-‐2/neu * Melatonin exhibits anti-‐inflammatory and anticancer effects and could be a chemopreventive and chemotherapeutic agent in human Her-‐2 positive MDA-‐MB-‐361 breast cancer cells. Melatonin markedly inhibited phosphorylation of PI3K, Akt, PRAS40, and GSK-‐3 proteins, thereby inactivating the PI3K/Akt signalling pathway. * It induces Apaf-‐1 expression, triggered cytochrome C release, and stimulated caspase-‐3 and caspase-‐9 activities and cleavage, leading to an activation of the Apaf-‐1-‐dependent apoptotic pathway. * It inhibits cell proliferation and induces apoptosis by simultaneously suppressing the COX-‐2/PGE2, p300/NF-‐κB, and 99 16/12/14 PI3K/Akt/signalling (Wang et al., 2012).
Other Pathways
Breast Cancer
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Bax and Bcl-‐2 * The balance between Bax and Bcl-‐2 in favour of the former. The ratio of Bax to Bcl-‐2 is a useful index to evaluate tumour apoptosis induced by Kupffer cells. An experiment by Chen et al., (2002) suggests that alteration of the ratio of Bax to Bcl-‐2 may result from increased levels of iNOS and TNFα. * The combined assessment of Bcl-‐2 and Bax protein expression may be used to predict a clinical response to chemoradiation therapy based on the Bax/Bcl-‐2 ratio determined before therapy. The Ki-‐67 index may be a useful predictor of this prognosis (Matsumoto et al., 2004).
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SZKJT * There are only a few mechanistic studies on the action of TCM formulas as anticancer agents. One study was on San Zhong Kui Jian Tang (SZKJT), a complex formula comprising 17 different herbs, that is used for cancer therapy in China. * SZKJT was found to induce the mitochondrial apoptotic pathway by changing Bax/Bcl-‐2 ratios, cytochrome c release and caspase-‐9 activation in two human breast cancer cell lines, MCF-‐7 and MDA-‐MB-‐231 (Hsu et al., 2006). * Mitochondrial oncoproteins, such as bcl-‐2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel pro-‐apoptotic molecules in order to circumvent chemoresistance (Del Poeta et al., 2002). [email protected]
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SZKJT * Thallus Eckloniae (kun bu) * Cortex Phellodendri (huang bai) * Rhizoma Anemarrhenae (zhi mu) * Radix Platycodi (Jie Geng) * Rhizoma Sparganii (san leng) * Rhizoma Curcuma (e zhu) * Fructus Forsythiae (lian qiao) * Rhizoma Coptidis (Huang Lian) * Radix Glycyrrhizae Preparata (zhi gan cao)
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* * * * * * * * * 103
Radix Scutellariae (huang qin) Radix Paeoniae Alba (bai shao) Radix Puerariae (ge gen) Radix Bupleuri (chai hu) Extremitas Radix Angelicae Sinensis (dang gui wei) Radix Gentianae (long dan cao) Radix Cimicifugae (sheng ma) Radix Trichosanthis (tian hua fen) Rhizoma Zingiberis (sheng jiang) 16/12/14
Leonurus japonicus (yi mu cao) * Data suggest that leonurus aqueous & ethanol extract may effectively inhibit the proliferation of breast cancer cells through mechanisms of both cytotoxicity and cell cycle arrest. The cellular effects of the extract are non-‐apoptotic and ER independent on breast cancer cells. * The 70% ethanol extract in vivo markedly suppressed the development of uterine adenomyosis and mammary cancers, while the aqueous extract was previously reported to have anti-‐cancer activity in breast cancer cells with low potency (Tao et al., 2009).
[email protected]
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Shenqi Fuzheng Injection * In regard to advanced breast cancer, the herbal preparation Shenqi Fuzheng Injection (SFI), was demonstrated to alleviate bone marrow inhibition and cellular immunity suppression caused by chemotherapy, and to relieve clinical symptoms, raise the quality of life and prolong survival time compared to patients receiving only chemotherapy. * The total short-‐term remission rate, the improvement rate of clinical syndrome and quality of life was 50.0%, 70.0% and 76.7% in the treatment group, and 43.3%, 46.7% and 50.0% in the control group, respectively, showing significant difference between the two groups (all P < 0.05). [email protected]
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Shenqi Fuzheng Injection * The occurrence of adverse reaction in the treatment group was lower than that in the control group (P < 0.05). The level of CD3+ CD4+ and CD4+/CD8+ ratio increased (P < 0.05) and CD8+ decreased in the treatment group (P < 0.01), while they showed insignificant change in the control group (Huang et al., 2008). * SFI can improve and regulate immune function of the patients with local advanced breast cancer given the neoadjuvant chemotherapy, and therefore it can enhance the curative effect and reduce the side effect as well. An obvious rise of the T-‐lymphocyte subgroup and NK cells was found in the study group after the neoadjuvant chemotherapy, with a very 16/12/14 significant difference from the 106 controls (P < 0.01).
Shenqi Fuzheng Injection * Shenqi Fuzheng is a newly developed injection concocted from two kinds of Chinese medicinal herbs: Radix Astragali (huang qi) and Radix Codonopsis (dang shen) (Yang & Xu, 2004; Lu & Lu, 2006). * It was approved by the State Food and Drug istration of the People’s Republic of China in 1999 primarily as an antitumour injection to be manufactured and marketed in China (Zhong, 2009).
[email protected]
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MDR Breast Cancer * Paris saponin VII (PS VII), a kind of saponin, from Trillium tschonoskii (yan ling cao) dose dependently suppressed cell viability as well as triggered apoptosis and modulated drug resistance of MCF-‐7/ADR cells. * Further results showed that PS VII treatment in MCF-‐7/ADR cells led to increased TNFR1, TRAIL R1/DR4, TRAIL R2/DR5, and FADD expression, and activation of PARP, caspase-‐8, and 3. In parallel to the alterations, P-‐glycoprotein expression and activity were also reduced. * These findings showed that PS VII might be an effective tumouristatic agent for the treatment of MDR breast cancer (Li et al., 2014). [email protected]
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Breast METS * MDA-‐MB-‐231 cell line is a highly metastatic breast cancer cell line. The results demonstrated by Kim et al., (2008) that treatment with berberine inhibits growth in both MDA-‐MB-‐231 and MCF-‐7 cells. This partly occurs through the induction of apoptosis in MDA-‐MB-‐231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-‐7 cells. * Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, Yeh, Wu & Yen (2010) observed that ursolic acid exerted a dose-‐ and time-‐dependent inhibitory effect on the migration and invasion of highly metastatic breast MDA-‐MB-‐231 cells at non-‐cytotoxic concentrations. [email protected]
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Breast METS * The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-‐κB, urokinase-‐type plasminogen-‐activator (u-‐PA), matrix metalloproteinase 2 (MMP-‐2), and matrix metalloproteinase 9 (MMP-‐9) (Ho et al., 2009; Hamsa & Kuttan. (2011) * Reduction of Rho kinase-‐mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-‐2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011) * Down-‐regulation of hypoxia-‐inducible factor 1 (HIF-‐1), vascular endothelial growth factor (VEGF) and pro-‐inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012). 110
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Breast METS * Berberine also inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell-‐cycle arrest. Anoikis, or detachment-‐induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localised cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis. * The anoikis-‐resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine in both the adherent and anoikis-‐resistant cell lines. Berberine promoted the growth inhibition of anoikis-‐resistant cells to a greater extent than doxorubicine treatment (Kim et al., 2010). 111
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Panaxea Berberine Complex * Berberine is an anticancer agent by three different cell lines which were MCF-‐7, HepG-‐2, and Caco-‐2 cells by using neutral red uptake assay which compared with control normal cells (PBMC). Berberine chloride and barberry extract showed to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (Abeer et al., 2013). Berberine has been established to inhibit the growth of breast cancer cells. * Treatment with berberine-‐induced cell cycle arrest at G0/G1 in the anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 cells as compared to untreated control cells. These results revealed that berberine can efficiently inhibit growth by inducing cell cycle arrest in anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 cells (Kim et al., 2010). 112
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Panaxea CoryBer * Gao et al., (2008) found that the yanhusuo extract inhibited the migration and invasion of MDA-‐MB-‐231 cells in vitro. The yanhusuo extract inhibited the mRNA expression and activity of metalloproteinase-‐9 (MMP-‐9). The anti-‐cancer metastasis effect of yanhusuo involved the activation of p38 and inhibition of ERK1/2 and SAPK/JNK mitogen-‐activated protein kinase (MAPK) signalling. * Oh et al., (2010) identified the biological activity of yanhusuo against cancer metastasis. Corydalis alkaloid (CA) inhibited LPS-‐ induced IL-‐8 production in a dose-‐dependent manner. CA inhibited extracellular signal-‐regulated kinase and p38 MAPK phosphorylation, which suggests that CA inhibits IL-‐8 secretion 113 16/12/14 by blocking MAPK phosphorylation.
Panaxea CoryBer * Corydalis alkaloids containing Tetrahydropalmatine (dl-‐ thp) Rhizoma Coptidis Recens containing berberine (75%)
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Pain * Research suggests that dl-‐ THP blocks certain receptor sites (e.g., dopamine) in the brain to cause sedation. Reports from Chinese researchers have noted that the herb was effective in reducing pain in seventy-‐eight per cent of the patients tested (Oh et al., 2010). 114
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Breast METS * Hu et al., (2014) istered Chinese traditional herb drugs called Fei Decoction to help a patient with breast cancer multiple pulmonary and skeletal metastatic lesions. After taking the Chinese herbs for 2 months, the tumour marker (CEA, CA15-‐3) dramatically decreased, resulting in the normal range. * Both lung and bone metastatic sites reduced according to CT and ECT imaging, and the patient felt free from the complaint of pulmonary and cardiac discomfort. * The PFS (progression-‐free-‐survival) and TTP (time-‐to-‐ progression) from the onset to date is notable. [email protected]
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Fei Decoction * Semen Coicis (yi yi ren) * Semen Persicae (tao ren) Semen Benincasae (dong gua zi) * Radix Astragali membranaceus (huang qi) * Bulbus Lilii (bai he) * Cortex albiziae (he huan pi) Radix Ophiopogonis (mai men dong) * Rhizoma bletillae (bai ji) * Bulbus fritillariae cirrhosae (chuan bei mu)
* Semen Persicae (tao ren) Radix Platycodonis grandiflorum (jie geng) * Herba Houttuynia cordata (yu xing cao) * Radix Glehniae (bei sha shen) Radix Cynanchi atrati (bai wei) Radix Glycyrrhizae (gan cao) * Fructus Oryzae Germinatus Praeparata (jiao dao ya) * Fructus Hordei Germinatus Praeparata (jiao mai ya) 116 16/12/14
Hyperprolactinaemia * Prolactin levels were measured in 149 patients with advanced metastatic breast cancer and Hyperprolactinaemia occurs in 44% of patients with metastatic breast cancer in the course of the disease. HYPRL is associated with progressive breast cancer in 88% of cases. * It is concluded that HYPRL is of prognostic significance and a reliable indicator of progressive disease in advanced metastatic breast cancer (Holtkamp et al., 1984). * Hyperprolactinaemia is associated with aggressiveness of the tumour, early disease relapse or metastases, and poor overall survival in patients with node negative breast cancer (Patel et al., 1996). 117
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Hyperprolactinaemia * The formula Huiru Yizeng Yihao significantly decreased prolactin (PRL) and increased oestradiol (E2), progesterone (P), follicle stimulating hormone (FSH), luteinizing hormone (LH) concentrations of hyperprolactinaemia rats. * It decreased E2, PRL, FSH, gonadotropin-‐releasing hormone (GnRH), 5-‐hydroxytryptamine (5-‐HT) and increased P concentrations of human menopausal gonadotropin (hMG). * Treatment could significantly regulate the sex hormone disorder of hyperprolactinemia (Wang et al., 2013).
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Huiru Yizeng Yihao * Mai Ya (Fructus Hordei Germinatus) * Xia Ku Cao (Prunella vulgaris L.) * Bai Shao (Paeonia lactiflora) Pallas) * Zhe Bei Mu (Fritillaria thunbergii Miq. * Ru Xiang (Boswellia carterii Birdw.) * Yu Jin (Curcuma aromatica Salisb.) * Dan Shen (Salvia miltiorrhiza Bge.) * Bai Jie Zi (Semen Brassicae) * Mu Li (Ostrea gigas thunberg) * Kun Bu (Laminaria japonica Aresch.) [email protected]
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Magnolol * In this study, Liu et al., (2013) examined the effects of magnolol (Mag), a compound extracted from medicinal herbs, on breast cancer cells in vitro and in vivo. * Highly invasive cancer cells were found to be highly sensitive to treatment. Mag markedly inhibited the activity of highly invasive MDA-‐MB-‐231 cells. Furthermore, Mag significantly downregulated matrix metalloproteinase-‐9 (MMP-‐9) expression, an enzyme critical to tumour invasion. * Mag suppresses tumour invasion by inhibiting MMP-‐9 through the NF-‐κB pathway.
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Scutellaria Barbata * Scutellaria barbata (ban zhi lian) was used in women with metastatic breast cancer (MBC). The trial was an open-‐label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. * Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on Scutellaria barbata for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumour regression (Perez et al., 2010).
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Objective Tests for TCM Pattern
Pattern Syndrome 证 zhèng
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Genetic Polymorphisms * The genetic mechanisms underlying syndrome differentiation in patients. Twenty-‐nine single nucleotide polymorphisms (SNPs) in EGF, TGFA, and EGFR were investigated. * Two SNPs, rs11466285 in TGFA and rs884225 in EGFR, were significantly associated with the distribution of ZHENG. * The rs11466285 TT genotype increased the risk of damp heat with toxin (DHT) and deficiency of both Qi and yin (DQY) compared with obstruction of blood stasis (OBS).
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Genetic Polymorphisms * The rs884225 AA genotype could increase the risk of DQY and deficiency of both Qi and blood (DQB) compared with yin deficiency due to stomach heat (YDSH). * Parallel comparison among the SNPs and syndrome types revealed that DQB was distinct from YDSH, disharmony between the liver and stomach, stagnation of phlegm muddiness (SPM), OBS, and other syndromes at several SNP loci (Zhang et al., 2013)
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Toxic Heat and Chronic Inflammation
Inflammation
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Medicinal herbs for heat clearance and detoxification (清熱解毒藥) * Artemisia annua (qing hao) * Astragalus membranaceus (huang qi) * Coptidis Rhizoma (huang lian) * Erigeron breviscapus (deng zhan xi xin) * (Houttuynia cordata (yu xing cao) * Oldenlandia diffusa (bai hua she she cao) * Oroxylum indicum (gu zhi hua) [email protected]
* Paeonia suffruticosa (mu dan pi) * Paris polyphylla (zao xiu) * Patrinia scabiosaefolia (bai jiang cao) * Rabdosia rubescens (dong ling cao) * Scutellaria baicalensis (huang qin) * Scutellaria barbata (ban zhi lian) * Solanum nigrum (long kui) * Sophora flavescens (ku shen gen) * Vitex rotundifolia (man jing zi) 126 16/12/14
Chronic Inflammation * About 95% cancer can link modern life style and environment with inflammation as the basic underlying cause (Anand et al., 2008). Chronic or persistent tissue inflammation or irritation is correlated with adverse effects and has long been linked with increasing rate of tumour formation by epidemiological studies (Balkwill & Mantovani, 2001; Rossi & Sawatzky, 2008). * Rudolf Virchow (1821-‐1902) observed frequent cancer origination at the site of chronic irritation. His hypothesis was that some classes of irritants, together with the tissue injury and the ensuing inflammation caused enhanced cell proliferation (Parsonnet, 1999). [email protected]
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Chronic Inflammation * In China in the 7th Century, CE Chao Yuanfang (550-‐630) reported, while working as an imperial physician, “Qi and water stagnation stays in the body, clustering as nodules ('lumps’). Toxic Heat fights Zheng Qi in the body, stagnating and steaming the body, causing hypochondriac pain and fullness.”(Cultural China website) * The Zhu Bing Yuan Hou Lun (Treatise on Causes and Symptoms of Diseases, Vol. 12) was one of the first to mention Toxic Heat in regard to tumours (swellings) (Wong & Wu, 1932).
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Chronic Inflammation * Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases (Blanco et al, 2007). Mediators of the inflammatory response, (e.g. cytokines, free radicals, prostaglandins and growth factors) can induce genetic and epigenetic changes including point mutations in tumour suppressor genes, DNA methylation and post-‐translational modifications and this causes alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (Perwez-‐Hussain & Harris, 2007).
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Chronic Inflammation * In more recent times, Kevin Chan (1995) reports that the source of Toxic Heat is TNF-‐α, IL-‐6 and other inflammatory cytokines, combined with blood stasis, hypoxia and a weakened cellular (Th1) immunity. The concept of Toxic Heat in TCM is central to cancer treatments. * From a more orthodox position, Dalgleish and O’Byrne (2006, p. 5) state, “it is recognised that cancer is a series of stochastic events involving permanent activation of oncogene pathways and deletion of tumour suppressor genes, and in the face of chronic inflammation, immune induction does not occur and the mutated cell survives to divide”. [email protected]
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Chronic Inflammation * The tumour microenvironment consists of tumour, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumour progression and metastasis. * All intimately interact with one another and play an important role in inflammatory and pro-‐angiogenic processes and promote tumor cell proliferation. Interestingly, there is an association between chronic inflammation and tumour development or progression; 15% of all cancers are attributed to inflammatory aetiologies (Kuper, Adami , Trichopoulos, 2000). [email protected]
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Chronic Inflammation * Serum IL-‐6 concentration was significantly higher in patients with breast cancer compared to healthy controls. Serum IL-‐6 level is the most discriminative factor separating healthy controls and the loco-‐regional and metastatic breast cancer patient groups. * These results suggest a role for tumour-‐derived IL-‐6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF (Benoy et al., 2002).
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Oncogenes and Tumour Suppressor Genes * There are two classes of genes that can control cancer development. Oncogenes and tumour suppressor genes belong to one class, while the other class belongs to the caretaker genes. * Healthy cells follow standard rules of growth and proliferation, and have a definitive life span. In contrast, cells with an oncogenic activation undergo much faster cell division with an indefinite life span. Tumour suppressor genes are evolved to inhibit deregulated cell growth.
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NF-‐κB and p53 Antagonise Each Others Activity.
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The yin/yang of NF-‐kB/p53 * Various mediators involved in the pathways are indicated. In addition, p53 and NF-‐ κB can inhibit each other by direct physical interaction through their multimerisation domain. Eventually, the effect of activation NF-‐ κB pathway prevents the activation of p53 pathway and vice versa. KEY: The black coloured upward arrows adjacent to NF-‐ κB and p53 indicate activation of these transcription factors. MDM2: mouse double mute 2; β-‐Tr1: beta transducing repeat containing protein1; ARF: alternate reading frame of INK4/ARF locus; ATR: ATM-‐Rad3 related; CHK: check point kinase; I κB: inhibitor of kB; IKK: inhibitor of kappaB kinase. [email protected]
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NF-‐kB * Coix lachryma-‐jobi (yi ren) seeds is currently the most commonly used treatment for cancer in China and clinical data the use of this preparation of a TCM cancer treatment. Coix seed extract also significantly affects gene expression in cells, including downregulation of genes (such as COX-‐2 and matrixmetalloproteinases) that are considered to be important in neoplasia. * Coix extract inhibits activity of protein kinase C, a major mediator of signal transduction and activator of NF-‐kB (Woo et al., 2005).
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Cancer Stem Cells * The receptor CXCR1 is found on the cancer stem cells and triggers growth of stem cells in response to inflammation and tissue damage. Investigation has suggested an important link between inflammation, tissue damage and breast cancer, which may be mediated by cancer stem cells. * Furthermore, anti-‐inflammatory drugs may provide a means of blocking these interactions, thereby targeting breast cancer stem cells (Wicha 2010). Clearly, inflammation due to immune dysregulation plays a critical role in tumour initiation, progression and metastases.
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Cancer Stem Cells & EMT * Morel et al., (2008) show that cells possessing both stem and tumourigenic characteristics of “cancer stem cells” can be derived from human mammary epithelial cells following the activation of the Ras-‐MAPK pathway. The acquisition of these stem and tumorigenic characters is driven by epithelial-‐ mesenchymal transition (EMT) induction. * Overexpression of MMP-‐9 resulted in induction of the EMT in these cells and this could be reversed by treating with luteolin or quercetin. Co-‐treatment with epidermal growth factor (EGF) plus luteolin or quercetin resulted in a more epithelial-‐like morphology, led to reduced levels of EGF-‐ induced markers of EMT, and caused the restoration of cell– cell junctions (Lin et al., 2011). [email protected]
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TNFα * Tumour necrosis factor-‐alpha (TNFα) has been implicated in both cancer development and progression in some preclinical models. In particular, as a central mediator of inflammation, TNFα might represent one of the molecular links between chronic inflammation and the subsequent development of malignant disease. * Furthermore, deregulated TNFα expression within the tumour microenvironment appears to favour malignant cell tissue invasion, migration and ultimately metastasis formation (Mocellin & Nitti, 2008).
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Inflammatory Cytokines * Tumour initiation, growth and progression and many of these effects are mediated by proinflammatory cytokines. Among these cytokines, the pro-‐tumourogenic function of TNFα, interleukin 6 & 1 (IL-‐6, IL-‐1) is well established (Akira et al., 1990). * Expression patterns of TNFα, IL-‐1beta, IL-‐6 and IL-‐10, along with transforming growth factor beta (TGF-‐β) , were similar in both parental and transformed cells. Considering all these results, we conclude that various cytokines have discrete roles in tumour promotion and cell transformation (Suganuma et al., 2002). [email protected]
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Inflammatory Cytokines * Chronic pathological inflammation is mediated via the continuing presence of a persistent stimulus, such as tumour cells, and the resulting prolonged inflammatory cytokine exposure has the potential to promote tumour growth through the induction of angiogenesis, DNA damage, and other events favourable to tumour invasion and metastases (Balkwill & Mantovani, 2001). Tumours produce their own inflammatory factors. [email protected]
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VEGF * Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. * Elevated VEGF blood concentrations have been proven to be associated with poor prognosis in human neoplasms. This finding is generally explained as a consequence of the potential angiogenic properties of VEGF itself. However, preliminary experimental studies suggest that VEGF, in addition to its angiogenic activity, may also play an immunosuppressant role by inhibiting dendritic cell (DC) maturation (Lissoni et al., 2001). 142 16/12/14
Herbs for Inflammation * Sumu (Lignum Sappan, 苏⽊木) was first mentioned in Xin Xiu Ben Cao (Newly Revised Materia Medica) by Su Jing in 657-‐659 CE and its action are said to ‘activate Blood’, ‘open channels and relieve pain’. * The aqueous extract of Lignum sappan (AELS) may markedly decrease the level of TNF and IL-‐6 (Wang et al 2007), it has also been shown it can kill cancer cell lines of HL-‐60, K562, L929 and Yac-‐1 at the concentration of 2μl/ml in vitro. The survival time of mice treated with AELS is increased by 185% (P0.01) by ip 0.2ml/mouse×7d (Ren & Zhang 1990).
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Herbs for Inflammation * Radix Pulsatillae (bai tou weng) use goes back to the Shen Nong Ben Cao Jing (2nd CE) and is said to ‘clear Heat’ and ‘eliminate Toxin’. It strongly inhibits the secretion of TNF, IL-‐1 and IL-‐6 from Kupffer cells [KC] stimulated by Lipopolysaccharide [LPS] (Hu et al, 2010). * Xian and Qian (2009) state that bai tou weng is an “innovative antitumour-‐drug of high effect and low toxin”. Triterpenoid Saponins isolated from Pullsatilla Root appear to be an important promoiety for the enhancement of anticancer activity of their aglycones (Bang et al 2007).
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Herbs for Inflammation * Herba Portulacae oleracea (ma chi xian) may act on adipose cells damaged by the high lipid serum to increase cell viability and lower the levels of TNF-‐α and IL-‐6 secreted by adipose cell secreted (Xiao et al, 2005). Its use is first mentioned in Xin Xiu Ben Cao and is said to ‘clear Heat’ and ‘eliminate toxin’ and also ‘cools Blood’ and stops bleeding. * Supernatant TNF-‐α and IL-‐6 decrease significantly after Phytolacca acinosa (shang lu decoction) culture (Zhang et al, 2004) while Chrysanthemum indicum (ye ju hua) has an inhibitory effect on sIL-‐2R, IL-‐6 and TNF-‐α (Zhang et al, 2000).
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Herbs for Inflammation * The serum levels of TNF-‐α, IL-‐6 and IL-‐10 decrease following baicalin treatment (Liu et al 2006). The flavonoid baicalin, isolated from the dried root of Scutellaria baicalensis (huang qin) is widely used in the traditional Chinese herbal medicine for its anti-‐inflammatory, anti-‐pyretic and anti-‐hypersensitivity effects. * Apoptosis was enhanced by the combination treatment of baicalin and baicalein, which activated caspases-‐3 and caspase-‐9, downregulated the level of bcl-‐2 and upregulated the level of bax or p53 via the ERK/p38 MAPK pathway (Zhou et al., 2009). [email protected]
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Herbs for Inflammation * Baicalin with scutellarin (both from Scutellaria baicalensis), and two extracts purified from Salvia miltiorrhiza (dan shen) (SM-‐470, circulatory stimulant) and Camellia sinensis (Cam-‐300, antipyretic), and examined their anti-‐proliferation effects on the human breast cancer cell lines MCF-‐7 and T-‐47D. * All four compounds inhibited MCF-‐7 and T-‐47D cell proliferation, SM-‐470, Cam-‐300, scutellarin and baicalin inhibited the proliferation of human breast cancer cells as well as CAL-‐27 and FaDu cells (Franek et al., 2005).
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Herbs for Inflammation * Daidzein treatment resulted in decreases in cyclin D, CDK2, and CDK4, whereas the expression of CDK6 and cyclin E was unchanged. Daidzein treatment increased the expression of the CDK inhibitors p21Cip1 and p57Kip2. Thus, daidzein exerts its anticancer effects in human breast cancer cells via cell cycle arrest at the G1 and G2/M phases (Peterson & Barnes, 1991). * The isoflavones daidzein and genistein inhibited iNOS protein and mRNA expression and also NO production in a dose-‐ dependent manner. The results explain the pharmacological efficacy of flavonoids as anti-‐inflammatory compounds (Hämäläinen et al., 2007). [email protected]
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Celprotect * Radix Pueraria lobata (Ge Gen) (standardised Daidzein) * Semen Sojae Praeparatum (Dan Dou Chi) (standardised Glycitein) [Note: this methoxyisoflavone is GMO free] * Genista tinctoria (ran liao mu) (extract Genistein 99%) * Radix Scutellariae Baicalensis (Huang Qin) (standardised Baicalein) * Radix Scutellariae Baicalensis (Huang Qin) (standardised Baicalin) * Fructus Gardeniae Jasminoidis (Zhi Zi) (standardised Jasminoidin) [email protected]
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ICC
(Inflammation Control Compound) * Radix Stephania tetrandra (fen fang ji) contains extract 15% Tetrandrine, 5% Fangchinoline * Folium Urticae dioica extract * Folium Ocimum sanctum contains extract 2.5% Ursolic acid * Radix Zingiber officinale (sheng jiang) contains extract 20% gingerols * Gum Boswellia serrata contains extract 30% AKBA * EGCG * Terminalia chebulla (he zi) contains 150 extract Luteolin 90%
* Reduces various inflammatory mediators, including interleukin-‐6 (IL-‐6), IL-‐1 beta, TNF-‐α, prostaglandin E2 and leukotrienes. * Rare side-‐effects may include diarrhoea, skin rash, acid reflux and nausea and may be contraindicated in those with pre-‐existing gastritis or gastro-‐oesophagael reflux disease (GORD). 16/12/14
Luteolin * Luteolin, a plant-‐derived flavonoid, is thought to inhibit tumour growth due to its strong inhibitory effect on nuclear factor (NF)-‐κB. * Results suggest that AMPK activity is critical for the inhibition of cancer cell growth, possibly via modulation of NF-‐κB activity. Hwang et al., (2011) showed that luteolin treatment causes the release of reactive oxygen species (ROS) and that these intracellular ROS in turn mediate AMPK-‐NF-‐κB signalling in cancer cells. * Having multiple biological effects such as anti-‐inflammation, anti-‐allergy and anticancer, luteolin functions as either an antioxidant or a pro-‐oxidant biochemically (Yin et al., 2008). [email protected]
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Cryptotanshinone * Cryptotanshinone (CTSO) is a major constituent of tanshinones, which are extracted from the medicinal herb Salvia miltiorrhiza (dan shen) and have well-‐documented anti-‐ oxidative and anti-‐inflammatory effects. * CTSO can reduce prostaglandin E2 synthesis and reactive oxygen species generation catalysed by COX-‐2, without influencing COX-‐1, and is directed against enzymatic activity of COX-‐2 (Jin et al. 2006).
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Tanshinone IIA * Tanshinone IIA (Tan IIA) could serve as a potential selective oestrogen receptor modulator (SERM) to treat inflammation without increasing the risk of breast cancer. It exerts anti-‐ inflammatory effects by inhibition of iNOS gene expression and NO production, as well as inhibition of inflammatory cytokines IL-‐1β, IL-‐6, and TNF-‐α (Fan et al., 2009). * Tan IIA could also decrease the expression of TNF-‐α and activation of nuclear transcription factor-‐kappa B (NF-‐κB) (Ren et al., 2010)
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Panaxea Tanshins * Salvia Miltiorrhiza (contains extract Tanshinone IIA and Cryptotanshinone) Note: * TANSHINS significantly increase the activity of CYP1A2 in a dose-‐dependent manner. CTS can induce hepatic microsome CYP1A2 expression significantly, which indicates potential drug-‐drug interaction might occur when CTS is co-‐ istrated with those drugs metabolised by CYP1A2 such as Capecitabine / Capecitabine (Xeloda), Lapatinib / Lapatinib (Tykerb) * Long term use may increase DHEA-‐S [email protected]
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Blood Stasis
Coagulation Factors
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Blood Stasis * Drugs with the efficacy of modifying rheological properties of blood, blood vessels and their interactions are denoted by “haemorheologicals”. Drugs of anti-‐hyperviscosaemia, anti-‐ coagulants, anti-‐platelet drugs, anti-‐thrombotics, vasodilators, endothelial cell protectors and anti-‐arthrosclerosis should be considered as haemorheologicals due to the actions in keeping blood fliudity and in maintaining normal vascular functions. * Haemorheologicals are importance for and ageing and life-‐ threatening diseases. ‘Blood Stasis’ syndrome is a common pathological syndrome in the elderly. In traditional Chinese medicine, the treatment for the syndrome is by herbs which activates blood circulation to remove ‘Blood Stasis’ (Liao , 156 16/12/14 2000).
Blood Stasis * Clot formation on the tumour cells facilitates tumour cell spreading, improving the attachment to the endothelium and enhancing tumour cell survival and metastasis (Im et al., 2004). Platelets surrounding tumour cells release growth factors and chemokines (VEGF, ILGF1, TGF-‐β) that enhance tumour cell proliferation and angiogenesis (Gay & Felding-‐Habermann., 2011). * Direct interaction between platelets and tumour cells triggers Epithelial to mesenchymal transition (EMT) through platelet derived TGF-‐β/SMAD and NF-‐κB pathways (Labelle et al., 2011). Multiple mechanisms have the potential to contribute to metastasis enhancement by coagulation and platelet 16/12/14 aggregation by tumour cells. 157
Blood Stasis & NK Cells * The idea of using ‘immune tonics’ may be a fruitless pursuit. * The aggregation of platelets around tumour cells in tissue culture greatly diminishes the ability of Natural Killer (NK) cells to lyse cancer cells in culture (Bobek et al, 2005). * Consistent with these findings, activation of platelets and the presence of fibrinogen have been shown to help tumour cells to evade immune surveillance mechanisms, protecting them from killing by NK cells (Palumbo et al, 2005, 2007), by both physical means and through signalling that leads to NK quiescence (Stewart, Vivier & Colonna, 2006; Kopp, Placke & Salih, 2009). [email protected]
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Blood Stasis * Chinese herbal medicine contributes a great deal to the health of the Chinese nation. Blood stasis syndrome (BSS) is a significant pathological syndrome in TCM. * The approach of treatment for BSS is activating blood circulation to remove blood stasis (ABCRBS). Herbs of ABCRBS are a category of over 10% in the modern Chinese Pharmacopoeia (Volume I – Herbal Medicine volume). Medicinal for promoting blood circulation and eliminating stasis in cancer (活⾎血化瘀藥) * * * * * *
Curcumae longae (jiang huang) Curcumae wenyujin (yu jin) Leonurus japonicus (yi mu cao) Panax notoginseng (san qi) Rheum officinale (da huang) Salvia miltiorrhiza (dan shen)
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Achyranthes Longifolia (tu niu xi) Squama Manis (chuan shan jia) Caulis Spatholobu (ji xue teng) Rhizoma Sparganii (san leng) Rhizoma Curcumae (e zhu) Eupolyphaga (di bie chong)
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Pro Creation R Capsules * Radix Angelica sinensis (dang gui) * Radix Ligusticum wallichii (chuan xiong) * Radix Salvia miltiorrhiza (dan shen) * Semen Prunus persicae (tao ren) * Fructus Liquidamber taiwaniani (lu lu tong) * Fructus Gleditsia sinensis (zao jiao) * Radix Saussurea lappa (mu xiang) * Radix Paeonia lactiflora (chi shao) * Rhizoma Corydalis (yan hu suo) * Frucus Melia toosendan (chuan Lian zi) * Radix Bupleurum chinense (chai hu) [email protected]
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Blood Stasis Formulations * Xiongshao capsule: Rhizoma Ligustici Chuanxiong, Radix Paeoniae Rubrae (chi shao) * Taohongsiwu decoction: Semen Persicae (tao ren), Flos Carthami (hong hua), Rhizoma Ligustici Chuanxiong, Radix Angelica sinensis (dang gui), Radix Paeoniae Alba (bai shao), Radix Rehmanniae Praeparata (shu di) * Xue Fu Zhu Yu Tang: Semen Pruni Persicae (tao ren), Radix Ligustici Chuanxiong, Flos Carthami Tinctorii (hong hua), Radix Angelicae Sinensis (dang gui), Radix Paeoniae Rubrae (chi shao), Radix Cyathulae Officinalis (chuan niu xi), Radix Rehmanniae Glutinosae (sheng di), Radix Bupleuri (chai hu), Radix Platycodi Grandiflori (jie geng), Fructus Citri Aurantii (zhi 161 16/12/14 ke), Radix Glycyrrhizae Uralensis (gan cao)
Panaxea Blood Stasis Granule * Buyanghuanwu (BYHW) Granules: Radix Astragalus (huang qi), Semen Persicae (tao ren), Flos Carthami (hong hua), Rhizoma Ligustici Chuanxiong, Radix Angelica sinensis (dang gui), Radix Paeoniae Rubrae (chi shao), Pheretima / earthworm (di long) (All above: Liu et al., 2012) * BYHW is an historical and empirical formula that is now being researched extensively in China. This research includes cardiovascular system diseases including DVT, spinal injuries, motor and nervous system diseases including migraine, metabolic diseases, respiratory and digestive diseases, and cancer (see Panaxea research database). [email protected]
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ji xue teng * The Chinese herb Spatholobus suberectus (ji xue teng) is commonly prescribed to cancer patients. In this study, the anti-‐cancer effect of SS and its molecular mechanisms have been investigated. Cell growth assay showed that SS effectively inhibits tumour cell growth in a dose-‐dependent manner and experiments show that the efficiency of SS alone group was superior to docetaxel or to docetaxel and SS combined. * SS is a potential herb for cancer treatment by inhibiting tumour growth via induction of apoptosis and arrest of the cell cycle at G2/M phase (Wang et al., 2011). [email protected]
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Oridonin * Rabdosia rubescens (dong ling cao) is a Chinese medicinal herb used widely. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling (Tang & Eisenbrand, 1992). * RR and its extracts have been shown to be able to suppress disease progress, reduce tumour burden, alleviate syndrome and prolong survival in patients (Henan Medical Institute, 1978) * Oridonin, was isolated from RR and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1988; Zhou et al., 2007) 164
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Panaxea OriJi * Oridonin extract 40% * Supercritical extract of Spatholobus suberectus 60%
[email protected]
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Fibrosis * Fibrotic disorders of the liver, kidney and lung are associated with excessive deposition of extracellular matrix proteins and on-‐going coagulation-‐cascade activity. In addition to their critical roles in blood coagulation, thrombin and the immediate upstream coagulation proteases, Factors Xa and VIIa, influence numerous cellular responses that may play critical roles in subsequent inflammatory and tissue repair processes in vascular and extravascular compartments. * Coagulation proteases have also been shown to play a role in the pathogenesis of fibrosis (Chambers & Laurent, 2002).
[email protected]
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Fibrosis * Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Plasminogen activator inhibitor-‐1 (PAI-‐1) is a key serpin (Yuko et al., 2008). * Proteolytic degradation of extracellular matrix (ECM) components during tissue remodeling plays a pivotal role in normal and pathological processes including wound healing, inflammation, tumour invasion, and metastasis (Park et al., 1999). * Protease inhibitors are emerging as potentially therapeutic tools to treat cancer (DeClerck & Imren, 1994). [email protected]
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Fy)Brox * Quercetin (Flos Sophorae extract) * Baicalein Scutellaria baicalensis extract) * Baicalin (Scutellaria baicalensis extract) * Salvianolic Acid B (Salvia Miltiorrhiza extract) * Emodin (Rheum Palmatum extract) * Scutellaria Baicalensis (huang qin) * Salvia Miltiorrhiza (dan shen) * Rheum Palmatum (da huang)
* Anti-‐fibrotic in total collagen accumulation * Anti-‐nodule formation * ‘Blood Buster’ * Fibrosis, characterised by extracellular matrix (ECM) accumulation and disruption of normal tissue architecture, is the common cause of chronic failure of many organs 168
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Congested Interstitial Fluid & the Extracellular Matrix
Phlegm Damp
[email protected]
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Phlegm Damp * The phlegm-‐dampness constitution is one of the nine constitutions and is the most common type in constitution study. Genomics studies found four upregulated genes: COPS8, GNPDA1, CD52 and ARPC3; and six downregulated genes: GSPT2, CACNB2, FLJ20584, UXS1, IL21R and TNPO in the phlegm-‐dampness constitution. * Gene functional analyses on genes affecting the differences between the phlegm-‐dampness constitution and the balanced constitution indicated that people with phlegm-‐dampness have a much higher risk of obesity, metabolic syndrome, hypertension, hyperlipaemia and diabetes (Wang et al., 2013). [email protected]
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Phlegm Damp * E-‐cadherin (E-‐cad) is a subclass of the cadherin family that plays a major role in maintenance of intercellular junctions in epithelial tissues (Oka et al., 1993). * There is a significant difference in E-‐cad expression between the stagnation of phlegm-‐damp type and the deficiency in both qi and blood and the deficiency-‐cold of stomach and spleen types, where E-‐cad expression was high. * E-‐cad expression is relatively low in the internal obstruction of stagnant toxin type and the in-‐coordination between liver and stomach type, where tumour development and metastasis may be associated with low E-‐cad expression, or with low homogeneous adhesiveness between tumour cells (Sun et al., 2007). 171
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Phlegm Damp * It is suggested that cell dissociation in tumours is accomplished by loss of function or expression of the epithelial cell adhesion molecule E-‐cadherin, and through the activity of cell motility factors, like scatter factor. * A striking feature of metastatic cells is the considerable flexibility in their adhesive interactions with other cells or components of the extracellular matrix (Behrens, 1993). * Oka et al., (1993) found significant correlations between E-‐cad expression and clinicopathological features. The frequency of reduced E-‐cadherin expression (Rd type) was significantly higher in invasive ductal carcinomas (58%) and poorly differentiated carcinomas (84%) than in noninvasive and well-‐ 16/12/14 differentiated carcinomas. 172
Phlegm Damp * The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. * ECM is commonly deregulated and becomes disorganised in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis (Lu, Weaver, Werb, 2012). * A direct link between hypoxia and the composition and the organisation of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome (Gilkes, Semenza, Wirtz, 2014). 173 16/12/14
Phlegm Damp * Interactions between the cell and the ECM are critical in controlling the fate and behaviour of cancer cells. Alterations in either the ECM or in cellular events affect this interaction. give an overview of the role of cell–ECM interactions in cancer, with a particular focus on the reciprocal nature of the cell–ECM interactions and how this contributes to cancer progression (van Dijk, Göransson, Strömblad, 2013). * Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer (Oskarsson, 2013). 174
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Phlegm Damp * Much of the mass of a solid tumour is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumourigenic processes. * One of the processes that is vital to tumour growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro-‐ and antiangiogenic factors that control tumour angiogenesis in a tightly regulated fashion (Campbell et al., 2010). 175
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Cell Adhesion Molecules * Cell adhesion molecules (CAMs) are proteins located on the cell surface involved in binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion. * Integrins, one of the major classes of receptors within the ECM, mediates cell-‐ECM interactions with collagen, fibrinogen, fibronectin, and vitronectin. Integrins provide essential links between the extracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such as apoptosis, differentiation, survival, and transcription. * The extracellular domain has major repeats called extracellular cadherin domains. Sequences involved in Ca2+ binding between the ECDs are necessary for cell adhesion. [email protected]
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ECM
* In biology, the extracellular matrix (ECM) is a collection of extracellular molecules secreted by cells that provides structural and biochemical to the surrounding cells. * Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-‐to-‐cell communication and differentiation are common functions of the ECM (Abedin & King, 2010) [email protected]
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Interstitial Fluid * Interstitial fluid is a solution that bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular fluid. The interstitial fluid is found in the interstitial spaces, also known as the tissue spaces. * Interstitial fluid bathes the cells of the tissues. This provides a means of delivering materials to the cells, intercellular communication, as well as removal of metabolic waste. * Extravascular or interstitial factors may contribute significantly to the inflammatory process including production of IL-‐6(doi: 10.1113/jphysiol.2011.206136) [email protected]
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Interstitium * The interstitium or interstitial space describes the space outside the blood and lymphatic vessels. It contains two phases; the interstitial fluid (IF) and the extracellular matrix. It consists of a solid or matrix phase and a fluid phase (Gel/ Sol) together constituting the tissue microenvironment. * Accumulated data show that tumour interstitial fluid (IF) is hypoxic and acidic compared with subcutaneous IF and plasma, and that there are gradients between IF and plasma giving information on where substances are produced and thereby reflecting the local microenvironment.
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Phlegm Damp * Is Phlegm Damp or hidden phlegm a disregulation of fluids and the attendant components? * Among the several different forms of cell interactions known to exist in multicellular organisms intercellular communication provides the most direct form of communication by allowing free exchange of ions and small molecules between neighbouring cells via permeable membrane junctions. This type of communication has been implicated in various biological functions such as cell differentiation, embryonic development, and tissue growth regulation (Azarnia & Larsen, 1977). * There is a significance in cell junction dysregulation in cancer. [email protected]
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MMTV-‐Wnt-‐1
Mammary Tumour Virus
[email protected]
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MMTV-‐Wnt-‐1 * In human breast cancers, a phenotypically distinct minority population of tumourigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumour growth. Studies suggest that there is a cancer stem cell compartment in the MMTV-‐Wnt-‐1 breast tumours (Cho et al., 2008). * The expression of the Wnt-‐1 proto-‐oncogene can induce mammary hyperplasia and tumourigenesis in the absence of ERα in females and in males.
[email protected]
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Ursolic Acid * All ursolic acid (UA) doses decreased tumour cell proliferation and UA at 0.10% mg/kg body weight/day was most effective in inhibiting tumour take and decreasing final tumour size. Modulation of Akt/mTOR signalling and induction of apoptosis appeared to mediate these effects on tumour growth. * UA potently disrupted cell cycle progression and induced necrosis in a clonal MMTV-‐Wnt-‐1 mammary tumour cell line in vitro. This study s the potential of UA as an anti-‐ tumourigenic agent (De Angel et al., 2010).
[email protected]
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Stage 0 Pre-‐cancerous lesions
DCIS & LCIS
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DCIS * Ductal carcinoma in situ (DCIS) is encountered much more frequently in the screening population compared to the symptomatic setting. The behaviour of DCIS is highly variable and this presents difficulties in choosing appropriate treatment strategies for individual cases. DCIS s for 5 to 20% of ‘cancers’. * Untreated, up to 50% of DCIS lesions progress to invasive disease, and that the time for progression may be up to four decades (Saunders et al, 2005; Collins et al., 2005). * Ten years after DCIS diagnosis, 98% to 99% of women will be alive. [email protected]
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DCIS Interventions * The natural history of DCIS remains to be elucidated, and it is unclear whether all DCIS cases progress to invasive breast cancer. Surgery plus radiation therapy or mastectomy is recommended for women in whom this potentially non-‐ progressive cancer is detected. * Regina Dehen (2013) s the developing trend toward active surveillance in lieu of breast-‐disfiguring surgery and offers evidence that CAM therapies including herbs and acupuncture may be of value in preventing progression of DCIS to invasive breast cancer.
[email protected]
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DCIS Interventions * Yanghe Huayan Decoction (YHD) Cornu Cervi Degelatinatium (lu jiao shuang) 12 g, prepared rhizome of rehmannia (shu di) 9 g, Cortex Cinnamomi (rou gui) 6 g, Semen Sinapis (bai jie zi) 3 g, Radix Curcumae (yu jin) 12 g, Psuedobulbus Cremastrae (shan ci gu) 15 g, Bulbus Frittillariae Thunbergii (zhe bei mu) 9 g, licorice root (gan cao) 6 g at the daily dose of 7.2 g/kg. * YHD could partially inhibit and reverse canceration of DCIS. It also could inhibit ki67 protein and mRNA expression. Its effect was similar to tamoxifen. * It is suitable for prevention and treatment of precancerous lesions of breast cancer (Li et al., 2014). 187
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Panaxea Cruciferous * DIM is a new class of ERβ-‐selective compounds, because it does not bind to ERβ, but instead it selectively recruits ERβ and co-‐activators (Vivar et al, 2010) * DIM can induce apoptosis in breast cancer cells independent of oestrogen receptor status by a process that is mediated by the modulated expression of the Bax/Bcl-‐2 family of apoptotic regulatory factors (Biochemical Pharmacology 2002). * I3C acts through a pathway that is distinct from either DIM or tamoxifen in regulating CDK2 enzymatic activity (The Journal of Biological Chemistry 2005). [email protected]
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Panaxea Cruciferous * DIM-‐treated subjects, relative to placebo, showed a significant increase in levels of 2-‐OHE1, DIM, and cortisol, and a non-‐ significant increase of 47% in the 2-‐OHE1/16alpha-‐OHE1 ratio from 1.46 to 2.14. In this pilot study, DIM increased the 2-‐ hydroxylation of oestrogen urinary metabolites (Dalessandri et al., 2004). * Results of a study by Nicastro et al., (2013) demonstrate the important role of hepatocyte growth factor (HGF) and c-‐Met (also called hepatocyte growth factor receptor) in DIM's anti-‐ proliferative effect on breast cancer cells and suggest that DIM could have preventive or clinical value as an inhibitor of c-‐ Met signalling. [email protected]
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Empirical and Researched Formulas
Breast Cancer Granules for Stages
[email protected]
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Stages * Breast cancer staging using the TNM system is based on the size of the tumour (T), whether or not the tumour has spread to the lymph nodes (N) in the armpits, and whether the tumour has metastasised (M). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. The main stages are: * Stage 0 is a pre-‐cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). * Stages 1–3 are within the breast or regional lymph nodes. * Stage 4 is 'metastatic' cancer that has a less favourable prognosis (NCI: accessed Aug 2014). * The difference between the two classifications of grade and stage is that the former views the status from pathology and the latter views it from the cancer cell migration. [email protected]
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Stages Stage
5 Year Survival
DCIS
93%
I
88%
IIA
81%
IIB
74%
IIIA
67%
IIIB
41%
IIIC
49%
IV
15%
Younger women tend to have a poorer prognosis than post-‐menopausal women due to several factors. Their breasts may change with their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts. There may also be biologic factors including greater inflammatory factors contributing to a higher risk of disease recurrence for younger women 16/12/14 with breast cancer (Peppercorn, 2009).
Empirical Formulas Cancer courses
Before operation 1. Liver Qi depression and phlegm stasis syndrome: Tiao Shen Gong Jian Tan 2. Turbid phlegm and blood stasis: Xue Yu Zhu Yu Tang and/or Xiao Yao Lou Bei San 3. Chong-‐Ren imbalance syndrome: Er Xian Tang. 4. Deficiency of the vital principle and poison blazing: Ba Zhen Tang w/ sheng di, mu dan pi, qing dai, shui niu jiao (ban mao, chan su) TCM indications and Chinese herbs (Lin et al., 2006) [email protected]
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Empirical Formulas Cancer courses
After operation 1. Syndrome of incoordination between spleen and stomach: Si Jun Zi Tang (not with ER+ tumours) 2. Two deficiency syndrome of Qi and blood (Yin): Ba Zhen Tang w/ mai dong, nu zhen zu (not with ER+ tumours) 3. Qi deficiency and blood stasis: Yi Qi Huo Xue Tang Period of consolidation 1. Two deficiency syndrome of Qi and blood (Yin): Yi Qi Yang Rong Tang 2. Deficiency of spleen and kidney: Jin Kui Shen Qi Wan 3. Chong-‐Ren imbalance syndrome: Er Xian Tang [email protected]
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Breast Cancer Stage 1
Pattern: Phlegm and qi Stagnation * Radix Angelicae Sinensis (dang gui) * Radix Paeoniae Lactiflorae (bai shao) * Radix Pseudostellariae (tai zi shen) * Sclerotium Poriae Cocos (fu ling) * Radix Bupleuri (chai hu) * Pericarpium Citri Reticulatae (chen pi) * Semen Trichosanthis (gua lou ren) * Bulbus Fritiliariae Cirrhosae (chuan bei mu) * Tuber Curcumae (yu jin) * Spica Prunellae Vulgaris (xia cu cao) * Rhizoma Iphigeniae Indicae (shan ci gu) [email protected]
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Breast Cancer Stage 2 & 3 Pattern: Heat and Blood Stasis
* Herba Taraxaci Mongolici cum Rd (pu gong ying) * Herba Solani Nigri -‐ Long Kui * Radix Arnebiae seu Lithospermi -‐ Zi Cao * Spica Prunellae Vulgaris -‐ Xia Ku Cao * Radix Trichosanthis Kirilowii -‐ Tian Hua Fen * Semen Vaccariae Segetalis -‐ Wang Bu Liu Xing * Pericarpium Citri Reticulatae Viridae -‐ Qing Pi * Bulbus Fritillariae Thunbergii -‐ Zhe Bei Mu * Radix Bupleuri -‐ Chai Hu * Fructus Viticis -‐ Man Jing Zi [email protected]
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Breast Cancer Stage 4
Pattern: Toxic Heat and qi & yin Deficiency * * * * * * * * * * * * *
Flos Lonicerae Japonicae -‐ Jin Yin Hua Herba Taraxaci Mongolici cum Rd -‐ Pu Gong Ying Rhizoma Paridis -‐ Zao Xiu Herba Scutellariae Barbatae -‐ Ban Zhi Lian Radix Rehmanniae Glutinosae -‐ Sheng Di Tuber Ophiopogonis Japonici -‐ Mai Men Dong Herba Dendrobii -‐ Shi Hu Radix Scrophulariae Ningpoensis -‐ Xuan Shen Radix Hibiscus -‐ Fu Rong Sclerotium Poriae Cocos -‐ Fu Ling Radix Pseudostellariae -‐ Tai Zi Shen Radix Astragali Membranacei -‐ Huang Qi Herba Gynostemma pentaphyllum -‐ Jiao Gu Lan
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Tests * Hyper coagulation: Fibrinogen, D-‐Dimer, Anti-‐thrombin III, and Plasminogen Activator Inhibitor 1 (PAI-‐1) and uPA * Tissue Factor (TF) and Blood Coagulation * Inflammation: C-‐reactive Protein, ESR (SED rate), IL-‐6 and TNFα, Serum amyloid A * Markers of Angiogenesis: Vascular Endothelial Growth Factor (VEGF), Interleukin (IL)-‐ 8, cathepsin B, Survivin, Matrix Metalloproteinases (MMP)-‐2 and 9, HIF-‐1a, Hepatocyte Growth Factor (HGF), epidermal growth factor (EGF) and its receptor EGFR, Fibroblast Growth Factor-‐2 (FGF-‐2) * Melatonin [email protected]
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Chemo, Radiotherapy, Tamoxifen & SEEMs, Immune Function, Aerobic Glycolysis, MDR
Additional Protocols
[email protected]
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Panaxea A1 Mark II * Angiogenesis is an essential event during the excessive growth and metastatic spread of solid tumours. Anti-‐angiogenic agents have become a new choice of therapy for patients with cancer. * In this study, Jiang et al., (2012) investigated the potential effect of Yangzheng Xiaoji (A1-‐ Mark2), a traditional Chinese medicinal formula presently used in the treatment of several solid tumours on angiogenesis. * It markedly inhibited in vitro tubule formation from vascular endothelial cells. They demonstrated that the extract has a concentration-‐dependent inhibitory effect on cell-‐matrix adhesion and cellular migration (Ye et al., 2012). [email protected]
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A1 Mark II * Radix Astragali (huang qi) * Fructus Ligustri Lucidi (nu zhen zi) * Radix Ginseng (ren shen) * Rhizoma Curcumae Ezhu (e zhu) * Fructificatio Ganodermatus (ling zhi) * Herba Gynostemma pentaphyllum (jiao gu lan) * Rhizoma Atractylodis Macrocephalae (bai zhu) * Herba Scutellariae Barbatae (ban zhi lian)
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A1 Mark II (continued)
* Herba Hedyotiolis Diffusae (bai hua she she cao) * Sclerotium Poriae Cocos (fu ling) * Eupolyphaga sinensis (di bie chong) * Endothelium Corneum Gigeriae Galli (ji nei jin) * Duchesnea indica (She Mei) * Herba Solani Lyrati (shu yang quan) * Herba Artemisiae Capillaris (yin chen Hao) * Radix Cynanchi Paniculatii (xu chang qing)
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Protocols Pre-‐chemo, radiotherapy and surgery * Strengthen qi and Blood * Clear qi Stagnation and Blood Stasis * Clear Phlegm * Clear Toxic Heat Concurrent to chemotherapy * Protect Essence & Warm Channels * Clear Toxins * Protect qi
Concurrent to radiotherapy * Protect yin & Fluids * Clear Heat Toxin Post chemo and radiotherapy * Tonify qi, Blood, yin / yang * Gently move qi and Blood
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Panaxea Chem1 Caps * Radix Panax ginseng (ren shen) * Radix Atractylodes macrocephala (bai zhu) * Rhizoma Dioscoreae (shan yao) * Root Inula helenium (tu mu xiang) ⼟土⽊木⾹香 * Pericarpium Citrus aurantium (zhi ke) [email protected]
* Fructus Amomum villosum (sha ren) * Radix Astragalus membranaceus (huang qi) * Semen Ziziphus jujuba var. spinosa (suan zao ren) * Radix Polygala tenuifolia (yuan zhi) * Radix Coptis chinensis (huang lian) * Radix Panacis Quinquefolii (xi yang shen) 204 16/12/14
Panaxea Chem1 Caps * Chem 1 caps has been found to have a number of effects on both innate and adaptive immune processes, with potential indirect anticancer activity in in vivo studies. No side effects were observed treated with the botanical compound, and no negative effects were observed on the response to chemotherapy or tumour mass. * No toxic effects were attributed by patients to the Chem 1 caps treatment, and 85% reported that they believed the botanical compound had helped reduce symptoms of breast cancer chemotherapy treatment (Rachmut et al., 2013).
[email protected]
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Panaxea CTF
(Chemotherapy Granules) * Radix Ginseng (ren shen) * Radix Codonopsis Pilosulae (dang shen) * Radix Astragali Membranacei (huang qi) * Radix Angelicae Sinensis (dang gui) * Folium Dichroae Febrifugae (shu di) * Radix Polygoni Multiflori – (he shou wu) * Gelatinum Corii Asini – (e jiao) * Fructus Lycii (gou qi zi) * Caulis Millettiae Reticulatae (ji xue teng) * Tuber Ophiopogonis Japonici (mai men dong) * Rhizoma Polygonati (huang jing) * Herba Leonuri Heterophylli (206 yi mu cao)
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Panaxea
CTF (Chemotherapy Granules)
(continued)
* Fructus Ligustri Lucidi (nu zhen zi) * Herba Dendrobii (shi hu) * Mori Albae Fructus (sang shen) * Herba Epimedii (yin yang huo) * Semen Cuscutae Chinensis (tu si zi) * Fructus Psoraleae Corylifoliae (bu gu zhi) * Sclerotium Cordyceps Chinensis (dong chong xia cao) * Herba Cynomorii Songarici (suo yang) * Fructus Alpiniae Oxyphyllae (yi zhi ren) * Radix Morindae Officinalis (ba ji tian) * Cortex Eucommiae Ulmoidis (du zhong) * Radix Salviae Miltiorrhizae (dan shen) 207
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Warburg Effect * Aerobic glycolysis is inefficient from the standpoint of ATP production, but it provides cancer cells with biomolecules implicated in the synthesis of lipids and nucleotides required for cellular proliferation. Thus, targeting aerobic glycolysis has clearly been recognized as a potentially fruitful approach for the treatment of cancer. * The inhibition of aerobic glycolysis by a combination of alpha lipoic acid and hydroxycitrate in Panaxea Synsergize effectively inhibits tumour development (Baronzio et al., 2012) Ingredients: * Alpha Lipoic Acid Hydroxycitric Acid 160 grams Powder Silica [email protected]
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Panaxea Synsergize * Eleven patients with advanced metastatic cancer from were treated with per os 0.4 to 1.8 g of lipoic acid and 1.2 to 3 g of hydroxycitrate during 2 to 21 months in addition to their normal chemotherapeutic regimen. Side effects occurred in half of the patients but were mild (grade 1-‐3) and limited to gastrointestinal disorders that disappeared on using proton pump inhibitors or decreasing the doses. Five patients were characterised by a partial regression, 3 by a stable disease, and 3 by disease progression. * Most of the patients receiving treatment for more than 6 months displayed partial regression or stabilisation. In conclusion Baronzio et al., (2012) found the results from these preliminary treatments that Synsergize can be used safely with various common standard chemotherapeutic regimens. [email protected]
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Panaxea MEGA EGCH * Additive and synergistic effects of EGCG when combined with conventional cancer therapies have been proposed, and its anti-‐inflammatory and antioxidant activities have been related to amelioration of cancer therapy side effects (Lecumberri et al., 2013). * Most cancers are believed to be initiated from and maintained by a small population of cancer stem-‐like cells (CSC) or tumour-‐initiating cells (TIC) that are responsible for tumour relapse and chemotherapeutic resistance. EGCG, the most abundant catechin in green tea, has been reported to induce growth inhibition and apoptosis in some cancer cells (Lin et al., 2012). [email protected]
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Chemotherapy Compounds * Coenzyme Q10 and L-‐Carnitine protect the heart * Vitamin E, L-‐Glutamine and B6 are neuro-‐protective * Omega 3 for Cachexia * Melatonin and IM1 mushroom extract protect the immune system * Coenzyme Q10 and multi-‐vitamin / mineral help with fatigue * Vitamin D3 is a chemotherapy agonist * Alpha Lipoic Acid is neuro-‐protective
[email protected]
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Panaxea RTF (Radiotherapy)
Heat and Dampness with yin & qi Deficiency * Herba Hedyotiolis Diffusae (bai hua she she cao) * Tuber Asparagi Cochinchinensis (tian dong) * Fructus Ligustri Lucidi (nu zhen zi) * Sclerotium Poriae Cocos (fu ling) * Sclerotium Polypori Umbellati (zhu ling) * Rhizoma Atractylodis Macrocephalae (bai zhu)
* Herba Agrimoniae Pilosae (xian he cao) * Tuber Curcumae (yu jin) * Rhizoma Dioscoreae Bulbiferae (huang yao zi) * Radix Astragali Membranacei (huang qi) * Radix Pseudostellariae (tai zi shen) * Flos Lonicerae Japonicae (jin yin hua) * Radix Glycyrrhizae Uralensis (gan cao) 212
RTF2
Radiotherapy * Astragalus membranaceous (huang qi) * Panax ginseng (ren shen, ginseng) * Angelica sinensis (dang gui) * Atractylodes macrocephala (bai zhu) * Bupleurum chinense (chai hu) * Cimicifuga foetida (sheng ma) * Glycyrrhiza uralensis (gan cao) * Citrus reticulata (chen pi)
* istration before irradiation protected the jejunal crypts (p < 0.0001), increased the formation of the endogenous spleen colony (p < 0.05) and reduced the frequency of radiation-‐ induced apoptosis (Kim et al., 2002)
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Radiotherapy Compounds * L-‐glutamine * Curcumin * Probiotics * Alpha-‐lipoic acid * Resveratrol * SOD (LIFE) * Coenzyme Q10
[email protected]
* Digestive enzymes * Jin Yin Hua * Melatonin * Silibinin * DIM/I3C * EGCG * Vitamin A / Retinol
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Panaxea POR
Post Operative Recovery * Radix Astragali Membranacei * Sclerotium Poriae Cocos (fu ling) (huang q)i * Pericarpium Citri Reticulatae (chen * Radix Pseudostellariae (tai zi pi) shen) * Radix Angelicae Sinensis (dang * Fructus Crataegi processed (jiao shan zha) gui) * Rhizoma Polygonati (huang jing) * Massa Medica Fermentata processed (jiao shen qu) * Caulis Millettiae Reticulatae (ji * Fructus Hordei Vulgaris Germinatus xue teng) processed (jiao mai ya) * Radix Paeoniae Rubrae (chi shao) * Fructus Lycii (gou qi zi) * Radix Rehmanniae Glutinosae * Radix Salviae Miltiorrhizae (dan (sheng di) shen) * Rhizoma Atractylodis * Fructus Ligustri Lucidi (nu zhen zi) Macrocephalae (bai zhu) * 215 Herba Epimedii (yin yang huo)
Panaxea IM1 (Immune Function) * Hericium erinaceus fruiting body * Maintains a correct balance extract 14:1 (hou tou) between cellular and * Maitake D fraction extract humoural immunity * Reishi -‐ Ganoderma lucidum (broken spore extract) * Astragalus membranaceus (huang qi) * Lentinula edodes/Shiitake extract (xiang gu) * Phellinus robiniae * Polyporus umbellatus (zhu ling) extract * Trametes versicolor (yun zhi) (extract) 216
Panaxea IM3 (Immune Function) * Cordyceps sinensis (contains extract purified polysaccharide) * Ganoderma lucidum (contains extract Ganopoly [30%]
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* Cellular immunity, cytotoxic, apoptotic, activates cellular and humoural immune response
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Panaxea AV/AT * Andrographolide treatment inhibited the proliferation of different tumour cell lines. The compound exerts direct anticancer activity on cancer cells by cell-‐cycle arrest at G0/G1 phase through induction of cell-‐cycle inhibitory protein p27 and decreased expression of cyclin-‐dependent kinase 4 (CDK4) (Rajagopal et al., 2003). * Immunostimulatory activity of andrographolide is evidenced by increased proliferation of lymphocytes and production of interleukin-‐2. Andrographolide also enhanced the TNF-‐α production and cluster of differentiation (CD) expression, resulting in increased cytotoxic activity of lymphocytes against cancer cells (Kumar et al., 2004). [email protected]
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Panaxea AV/AT * The polysaccharide fraction from Taraxii Herba, Taraxasterol showed potent immuno-‐potentiating activities with anti-‐ tumour activities. The fraction having small amount of protein inhibited the growth of solid tumour and increased peritoneal exudate cells and immuno-‐organ weights (Jeong et al., 2009). * Chlorogenic acid is a phenolic natural product isolated Flos Lonicera, is an antioxidant, an inhibitor of the tumour promoting activity of phorbol esters (Huang et al., 1988) and its active principles possess wide pharmacological actions, such as anti-‐inflammatory, antibacterial, antiviral, and antioxidative activities (Shang et al., 2011). [email protected]
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Panaxea AV/AT * Andrographolide from Andographis paniculata (chuan xin lian) * Taraxasterol from Taraxacum mongolicum (pu gong yin) * Chlorogenic Acid from Flos Lonicera (jin yin hua)
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* 3 isolates from commonly used Chinese herbs
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Tamoxifen * Tamoxifen induces cellular oxidative stress. Most breast cancer, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumour growth by tamoxifen, is unclear. * Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signalling pathways leading to the activation of activating protein-‐1 (AP-‐1), which in turn cause not only tamoxifen resistant breast cancer to develop, but lead to tamoxifen activated breast cancer.
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Panaxea BRC5
Tamoxifen Regulating Formula * Mori Albae Fructus (sang shen) * Cortex Moutan Radicis (mu dan pi) * Plastrum Testudinis (gui ban) * Fructus Ligustri Lucidi (nu Zhen Zi * Herba Ecliptae Prostratae (han lian cao) [email protected]
* Rhizoma Anemarrhenae Asphodeloidis (zhi mu) * Fructus Rosae Laevigatae (jin ying z)i * Calyx Diospyros Kaki (zhi di) * Radix Polygoni Multiflori (he shou wu) * Radix Panacis Quinquefolii (xi yang shen)
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Jia Wei Xiao Yao San * JWXYS is the most common Chinese medicine decoction co-‐ prescribed with tamoxifen (TAM) when breast cancer is treated by hormonal therapy. Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and TAM (Chen et al., 2014). * Among female breast cancer patients who had undergone TAM therapy, Chinese herbal products (CHP) consumption decreased the risk of subsequent endometrial cancer. Jia-‐ Wei-‐Xiao-‐Yao-‐San (Augmented Rambling Powder) and Shu-‐ Shu-‐Jing-‐Huo-‐Xue-‐Tang (Channel-‐Coursing Blood-‐Quickening Decoction) were the two most commonly used CHPs (Tsai et al., 2014). [email protected]
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Jia Wei Xiao Yao San * JWXYS is often co-‐prescribed with tamoxifen when breast cancer is treated by hormonal therapy (Lai et al., 2012). It is of note that some of the herbs in JWXYS are able to upregulate ERBB2 and ESR1 gene expression, while JWXYS alone does not induce any significant change in the expression of the above-‐mentioned genes. * Chui et al., (2014) attribute this to the fact that there are drug-‐ drug and drug-‐cell interactions between these components in JWXYS's composition. * Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam (Chen, et al., 2014). [email protected]
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Jia Wei Xiao Yao San * Radix Bupleuri (Chai Hu) * Radix Angelicae Sinensis (Dang Gui) * Radix Paeoniae Lactiflorae (Bai Shao) * Rhizoma Atractylodis Macrocephalae processed (Chao Bai Zhu) * Sclerotium Poriae Cocos (Fu Ling) * Radix Glycyrrhizae Uralensis (Zhi Gan Cao) * Rhizoma Zingiberis Officinalis Recens (Sheng Jiang) * Cortex Moutan Radicis (Mu Dan Pi) * Fructus Gardeniae Jasminoidis (Zhi Zi) * Herba Menthae Haplocalycis (Bo He) [email protected]
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Shu Gan Liang Xue (SEEMs) * Shu-‐Gan-‐Liang-‐Xue (SGLX) a classic formula was tested on endocrine therapy-‐ associated hot flashes symptom in breast cancer patients. * For hot flashes symptom, in Chinese herbs decoction istration group, 21.9% reported symptom disappeared, 68.7% reported symptom alleviated, 9.4% reported symptom not changed; in endocrine therapy alone group, 17.9% reported symptom disappeared, 46.4% reported symptom alleviated, 35.7% reported symptom not changed (Xue, Sun, Li, 2011). * SGLX decoction, having synergistic effect on TAM, can reduce serum hormone level and alleviate the endometrial hypertrophy side effect of TAM. The results suggest that SGLXD is a potential dual aromatase-‐ sulfatase inhibitor by simultaneously down-‐regulating the expressions of CYP19 and STS in MCF-‐7 and T47D cells (Fu & Li, 2011).
Shu Gan Liang Xue * SGLX showed dose-‐dependent inhibitory effect on the proliferation of ZR-‐75-‐1 cells with IC50 value of 3.40 mg/mL. It also suppressed the stimulating effect on cell proliferation of testosterone and oestrogen sulfates (E1S). Oral istration of 6 g/kg of SGLX for 25 days resulted in a reduction in tumour volume in non-‐ovariectomized and ovariectomised nude mice. * Results suggested that SGLX showed anti-‐tumour effect on breast cancer cells both in vitro and in vivo. The anti-‐tumour activity of SGLXD is related to inhibition of aromatase and STS gene via decreasing their expression. SGLX may be considered as a novel treatment for ER positive breast cancer (Zhou et al., 2014).
Shu Gan Liang Xue * Shu-‐Gan-‐Liang-‐Xue Decoction (SGLX), a Chinese herbal formula, acts as a selective oestrogen enzyme modulators (SEEMs) agent by down-‐regulating the expression of Steroid sulfatase (STS) in the levels of transcript and enzymatic activity. * In view of the aforementioned characteristics, SGLX could serve as a novel therapeutic treatment to combat hormone-‐ dependent breast cancer (HDBC) (Zhang & Li, 2010). * SEEMs: clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene
Panaxea SEEMs (SGLX) * Radix Lithospermi (zi cao gen) * Cortex Moutan Radicis (mu dan pi) * Fructus Schisandrae Chinensis (wu wei zi) * Radix Paeoniae Alba (bai shao) * Radix Bupleuri Chinensis (chai hu) * Radix Curcumae Wenyu-‐jin (yu jin) * Radix Cynanchi Atrati (bai wei)
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Tamoxifen Paper * Drug Herb Interactions: Tamoxifen * http://www.elotus.org/content/drug-‐herb-‐interactions-‐ tamoxifen-‐mm-‐van-‐benschoten-‐omd * M.M. Van Benschoten: [email protected]
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Multi-‐Drug Resistance * MDR is defined as insensitivity of cancer cells to cytotoxic and cytostatic actions of a number of structurally and functionally unrelated drugs. Cancer cells are intrinsically resistant to anti-‐ cancer agents because of genetic and epigenetic heterogeneity. * Also, there are some host factors which include poor absorption, rapid metabolism and excretion that can result in low serum drug levels. The mechanisms include alteration in the expression of proteins involved in the apoptotic signalling such as p53, Bcl2 family of proteins
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Multi-‐Drug Resistance * Multidrug-‐resistance (MDR) is the chief limitation to the success of chemotherapy. According to the National Cancer Institute, multidrug-‐resistance is a phenomenon where cancer cells adopt to anti-‐tumour drugs in such a way that makes the drugs less effective. Studies have shown that 40% of all human cancers develop MDR. * Deaths due to cancer occur in most of the cases when the tumour metastasises. Chemotherapy is the only choice of treatment in metastatic cancer, and MDR limits that option. * Chemotherapy kills drug-‐sensitive cells, but leaves behind a higher proportion of drug-‐resistant cells. As the tumour begins to grow again, chemotherapy may fail because the remaining 232 16/12/14 tumour cells are now resistant.
Multi-‐Drug Resistance * Ginsenosides * Rg3 reversed multi-‐drug resistance and restored the sensitivity of resistant KBV20 cell line to various anticancer drugs. Increased animal life span in an in vivo MDR model in a dose-‐independent manner (Kim SH et al, 2003; Yue et al, 2006). * Combination of purified saponins containing Rb1, Rb2, Rc, Rd, Re and Rg1 reversed MDR (Liu et al, 2008; Si & Tien, 2005) — Quercetin/Kaempferol
* Quercetin is less potent than kaempferol but more effective than genistein and daidzein in reversing MDR (Kioka et al, 1992). * Quercetin reverses MDR through action on mitochondrial membrane potential and the induction of apoptosis (Kothan et al, 2004)
* Puerarin * Down-‐regulates MDR1 expression via nuclear factor κ-‐B and CRE (cAMP response element) transcriptional activity (Hien et al, 2010) 233
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Multi-‐Drug Resistance * Curcumin * Enhances sensitivity to vincristine by the inhibition of P-‐gp in SGC7901/VCR cell line (Chang et al, 2006). * Curcumin derivatives reversed MDR by inhibiting P-‐gp efflux (Tang et al, 2005) * Curcumin derivatives reversed MDR by inhibiting P-‐gp efflux (Limtrakul et al, 2004).
* Honokiol * Down-‐regulates expression of P-‐glycoprotein at mRNA and protein levels in MCF-‐7/ADR, a human breast MDR cancer cell line (Xu et al, 2006)
* Quercetin * Inhibits overexpression of P-‐gp mediated by arsenite (Kioka et al, 234 16/12/14 1992).
Blood Stasis & qi Stagnation
Pain
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Herbal Hot Compress Treatment * Chuan Wu (Radix Aconiti) 100g * Advanced breast cancer pain poultice * Xi Xin (Herba Asari) 50g * Qing Pi (fructus citri reticulatae * All herbs are ground into powder, mixed with vinegar immaturus) 50g to make a paste, applied * Chuan Xiong (Rhizoma Ligustici directed on the lesion, and Chuanxiong) 50g then fixed with plastic * Ma Huang (Herba Ephedrae) 50g material. * Bing Pian (Borneolum * Apply hot compresses for Syntheticum) 50g 10–30 min to alleviate the * Zhang Nao (camphor) 50g pain * Gan Cao (Radix Glycyrrhizae) 50g 236
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Panaxea Free Movement * Gentiana macrophylla (qin jiao) * Salvia miltorrhiza (dan shen) * Panax notoginseng (san qi) * Storax Styrax (su he xiang) * Ligusticum Chuanxiong (chuan xiong) * Prunus persica (tao ren) * Carthamus tinctorius (hong hua) * Myrrha (mo yao)
* Notopterygium incisum (qiang huo) * Angelica sinensis (dang gui) * Citrus aurantium (zhi ke) * Tribulus terrestris (bai ji li) * Cyperus rotundus (xiang fu) * Stephania tetrandra (fen fang ji) * Achyranthes bidentata (chuan niu xi) * Manganese 237
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Jing Huo Xue Tang * Radix Ledebouriellae (fang feng) * Radix Notopterygium (qiang huo) * Radix Angelica Dahuricae (bai zhi) * Radix Rehmanniae (sheng di) * Radix Gentianae (long dan cao) * Poriae Cocos (fu ling) * Radix Clematidis (wei ling xian) * Rhizoma Atractylodes lancea (cang zhu)
* Pericarpium Citri Reticulatae (chen pi) * Rhizoma Ligustici Chuanxiong * Semen Persicae (tao ren) * Radix Cyathulae (chuan niu xi) * Radix Angelicae Sinensis (dang gui) * Radix Paeoniae Alba (bai shao) * Radix Stephaniae Tetandrae (han fang ji) * Radix Glycyrrhizae (gan cao) 238
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Zao Jiao Ci Ju Pi Mi Yin * Zao Jiao Ci (Spina Gleditsiae) * These formulation are to 30g invigorate the Blood, dissipate Blood Stasis, * Qing Pi (Pericarpium Citri promote movement of qi and Reticulatae Viride) 20g alleviate pain. * Chen Pi (Pericarpium Citri * They are beneficial for breast Reticulatae) 20g cancer patients with varying * Wang Bu Liu Xing Zi (Semen symptoms of Stagnant qi, Vaccariae 20g Stasis of Blood, and pain. * Yu Jin (Radix Curcumae) 15g * honey 30g [email protected]
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Cautions & Contraindications
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Cautions & Contraindications * Thirteen single herbal extracts and five compound recipes were found to increase either ERBB2 or ESR1 luciferase activity. * Si Wu Tang, Guan Xin Yin, and Suan Zao Ren Tang were found to increase either HER2 or ERα protein expression. In addition, Ligusticum chuanxiong was shown to have a great effect on ERBB2 gene expression and synergistically with oestrogen to stimulate MCF-‐7 cell growth. * Si Wu Tang reverses the antiproliferative effects induced by tamoxifen, including tumour weight, tumour volume, increased ERα expression, and N-‐cadherin expression (Chui et al., 2014) [email protected]
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Cautions & Contraindications * Silymarin is a mixture of polyphenolic flavonoids isolated from milk thistle (Silybum marianum) with anticancer activities reported for several organ sites. * The results showed that dietary silymarin increased the plasma concentration of free and total silibinin, a major component of silymarin, in a dose-‐dependent manner in the rat, but did not decrease either mammary tumour (MT) incidence or number. Instead silymarin modestly increased the number of 1-‐methyl-‐1-‐nitrosourea (MNU)-‐induced MTs in rats (Malewicz et al., 2006).
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This is only an introduction to the complex and artful application of Chinese herbal medicine to breast cancer
Thank You
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References * * * * * * * * * * * * * * * *
Abeer E Abd El-‐Wahab, Doaa A Ghareeb, et al. In vitro biological assessment of berberis vulgaris and its active constituent, berberine: antioxidants, anti-‐acetylcholinesterase, anti-‐diabetic and anticancer effects. BMC Complementary and Alternative Medicine 2013, 13:218 doi:10.1186/1472-‐6882-‐13-‐218 Abedin M, King N. Diverse evolutionary paths to cell adhesion. Trends in Cell Biology 2010 20 (12): 734–742. doi:10.1016/j.tcb. 2010.08.002. Akashi T, Saito N, Hirota H, Ayabe S. Anthocyanin-‐producing dandelion callus as a chalcone synthase source in recombinant polyketide reductase assay. Phytochemistry. 1997 Sep;46(2):283-‐7. Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). The FASEB Journal. 1990 vol. 4 no. 11 2860-‐2867 Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-‐2116. Axelson M, Kirk DN, Farrant RD, Cooley G, Lawson AM, Setchell KDR. The identification of the weak oestrogen equol [7-‐hydroxy-‐3-‐ (4′-‐hydroxyphenyl)chroman] in human urine. Biochem J. 1982;201:353–7. Azarnia R, Larsen WJ. Intercellular Communication and Cancer. Intercellular Communication 1977, pp 145-‐172 Bachg D, Haselhorst U. Effect of combined treatment with Haelan 951 in breast cancer cell line BT474. Townsend Lett 2007;5:73–84. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001, 357:539-‐545. Bang S-‐C, Kim Y, Lee J-‐H & Ahn B-‐Z. Triterpenoid Saponins from the Roots of Pulsatilla koreana. Journal of Natural Products. 2005, 68 (2), Pp. 268–72. DOI: 10.1021/np049813h Baronzio G, Schwartz L, Crespi E. Early clinical and toxicological results of a combination of natural glycolysis inhibitors on cancer patients. Biomedical Research 2012; 23: SI 219-‐223 Behrens J. The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res Treat. 1993;24(3):175-‐84. Benoy I, Salgado R, Colpaert C, et al. Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. Clin Breast Cancer. 2002 Jan;2(4):311-‐5. Bilal I, Chowdhury A, Davidson J, Whitehead S. Phytoestrogens and prevention of breast cancer: The contentious debate. World J Clin Oncol 2014; 5(4): 705-‐712 Available from: URL: http:// www.wjgnet.com/2218-‐4333/full/v5/i4/705.htm DOI: http:// dx.doi.org/ 10.5306/wjco.v5.i4.705 Biochemical Pharmacology. Volume 60, Issue 2, 15 July 2000, P244 ages 167-‐177. doi:10.1016/S0006-‐2952(00)00307-‐5 16/12/14 Biochemical Pharmacology. Volume 63, Issue 6, 15 March 2002, Pp 1085-‐97. doi:10.1016/S0006-‐2952(02)00856-‐0
References * * * * * * * * * * * * * *
Blanco D, Vicent, S, Fraga, MF, Fernandez-‐Garcia I, et al. Molecular analysis of a multistep lung cancer model induced by chronic inflammation. 2007 Neoplasia, 9(10),PP. 840–52. Bobek V, Boubelik M, Fiserova A, et al. Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung Cancer. 2005 47, 215–223. Byrne C, Divekar SD, Storchan GB, et al. Metals and breast cancer. J Mammary Gland Biol Neoplasia. 2013 Mar;18(1):63-‐73. doi: 10.1007/ s10911-‐013-‐9273-‐9. Campbell NE, Kellenberger L, Greenaway J, et al. Extracellular Matrix Proteins and Tumor Angiogenesis. Journal of Oncology. Volume 2010 (2010) http://dx.doi.org/10.1155/2010/586905 Cauley JA, Zmuda JM, Danielson ME, et al. Estrogen metabolites and the risk of breast cancer in older women. Epidemiology. 2003 Nov;14(6):740-‐4. Cavallini DC, Suzuki JY, Abdalla DS, et al. Influence of a probiotic soy product on faecal microbiota and its association with cardiovascular risk factors in an animal model. Lipids Health Dis. 2011 Jul 29;10:126. doi: 10.1186/1476-‐511X-‐10-‐126. Chambers RC, Laurent GJ. Coagulation cascade proteases and tissue fibrosis. Biochemical Society Transactions 2002, 30(2) Pp.194-‐200 DOI: 10.1042/0300-‐5127:0300194 Chan K. (1995). Progress in traditional Chinese medicine. Trends in Pharmacological Sciences, 16(6),Pp. 182–7. doi: 10.1016/S0165-‐6147(00)89019-‐7 Chang WH, Liu JJ, Chen CH, Huang TS, and Lu FJ: Growth inhibition and induction of apoptosis in MCF-‐7 breast cancer cells by fermented soy milk. Nutr Cancer 43, 214–226, 2002. Chen GG, Lai PBS, Hu X et al. Negative correlation between the ratio of Bax to Bcl-‐2 and the size of tumor treated by culture supernatants from Kupffer cells. Clinical & Experimental Metastasis 09-‐2002, Volume 19, Issue 5, pp 457-‐464 Chen Z, K. Gu, Y. Zheng, W. Zheng, W. Lu, and X. O. Shu. The use of complementary and alternative medicine among Chinese women with breast cancer. Journal of Alternative and Complementary Medicine, vol. 14, no. 8, pp. 1049–1055, 2008. Chen JP, Chiu SW, Chok HP, Wang Z, Zheng X, Lin Y: Prevention strategies for recurrence and metastasis of breast cancer by Chinese medicine. Global Traditional Chinese Medicine 2011, 4:125-‐128. Chen JL, Chang CJ, Wang JY, et al. In vitro and in vivo effects of Jia-‐Wei-‐Xiao-‐Yao-‐San in human breast cancer MCF-‐7 cells treated with tamoxifen. Integrative Cancer Therapies. 2014 Chi KH, Chiou TJ, Li , Chen SY, Chao Y. MS-‐20, A Chemotherapeutical Adjuvant, Reduces Chemo-‐Associated Fatigue and Appetite Loss in Cancer Patients. Nutr Cancer. 2014 Oct;66(7):1211-‐9. doi: 10.1080/01635581.2014.951731. Chiu JH, Chang CJ, Wu JC, et al. Screening to Identify Commonly Used Chinese Herbs That Affect ERBB2 and ESR1 Gene Expression 245 16/12/14 Using the Human Breast Cancer MCF-‐7 Cell Line. Evid Based Complement Alternat Med. 2014;2014:965486. doi: 10.1155/2014/965486.
References * * * * * * * * * * * * * * *
Cho RW, Wang X, Diehn M, et al. Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-‐Wnt-‐1 Murine Breast Tumors. STEM CELLS. Volume 26, Issue 2, pages 364–371, February 2008 Chung H, Jung Y-‐M, Shin D-‐H, et al. Anticancer effects of wogonin in both estrogen receptor-‐positive and -‐negative human breast cancer cell lines in vitro and in nude mice xenografts. International Journal of Cancer. 2008;122(4):816–822. Cohen I, Tagliaferri M, Tripathy D. Traditional Chinese medicine in the treatment of breast cancer. Semin Oncol. 2002 Dec;29(6): 563-‐74. Collins LC, Tamimi RM, Baer HJ, Connoly JL, Colditz GA, Schnitt SJ. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy. Results from the Nurses' Health Study. Cancer. 2005;103:1778–1784. doi: 10.1002/cncr.20979 Collins NH, et al. Characterization of Antiestrogenic Activity of the Chinese Herb, Prunella vulgaris, Using In Vitro and In Vivo (Mouse Xenograft) Models. Biol Reprod. Feb 2009; 80(2): 375–383. doi: 10.1095/biolreprod.107.065375. Cui Y, Shu X-‐O, Gao Yt, et al. Use of complementary and alternative medicine by Chinese women with breast cancer. Breast Cancer Research and Treatment. June 2004, Volume 85, Issue 3, pp 263-‐270 Cultural China (accessed 30 Aug 2014) http://history.cultural-‐china.com/en/50History3525.html Dai Z, Wan X, Kang H, et al. Clinical effects of shenqi fuzheng injection in the neoadjuvant chemotherapy for local advanced breast cancer and the effects on T-‐lymphocyte subsets. J Tradit Chin Med. 2008 Mar;28(1):34-‐8. Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3'-‐diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-‐stage breast cancer. Nutr Cancer. 2004;50(2):161-‐7. Dalgleish AG and O’Byrne K. Inflammation and Cancer: The Role of the Immune Response and Angiogenesis Pp.1-‐38 In The Link Between Inflammation and Cancer. Dalgleish AG and O’Byrne K Eds. Springer 2006. 10.1007/b137303 Darbre PD. Aluminium, antiperspirants and breast cancer. J Inorg Biochem. 2005 Sep;99(9):1912-‐9. De Angel RE, Smith SM, Glickman RD, Perkins SN, Hursting SD. Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutr Cancer. 2010;62(8):1074-‐86. doi: 10.1080/01635581.2010.492092. DeClerck YA, Imren S. Protease inhibitors: Role and potential therapeutic use in human cancer. European Journal of Cancer. Volume 30, Issue 14, 1994, Pp 2170–80 DOI: 10.1016/0959-‐8049(94)00460-‐M Dehen R. Regression of ductal carcinoma in situ after treatment with acupuncture. J Altern Complement Med. 2013 Nov;19(11): 911-‐5. doi: 10.1089/acm.2012.0696. Del Poeta G et al. The amount of spontaneous apoptosis detected by bax/bcl-‐2 ratio predicts outcome in acute myeloid leukemia 246 16/12/14 (AML). Blood. 2002 doi:10.1182/blood-‐2002-‐06-‐1714
References *
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Fan G-‐W, Gao X-‐M, Wang H, et al. The anti-‐inflammatory activities of Tanshinone IIA, an active component of TCM, are mediated by estrogen receptor activation and inhibition of iNOS. The Journal of Steroid Biochemistry and Molecular Biology. Volume 113, Issues 3–5, February 2009, Pages 275–280 Franek KJ, Zhou Zt, Zhang W-‐D & Chen WY. In vitro studies of baicalin alone or in combination with Salvia miltiorrhiza extract as a potential anti-‐cancer agent. International journal of oncology. 2005, vol. 26, no1, Pp. 217-‐24. Fu X-‐s & Li P-‐p. Shu-‐Gan-‐Liang-‐Xue Decoction Simultaneously Down-‐regulates Expressions of Aromatase and Steroid Sulfatase in Estrogen Receptor Positive Breast Cancer Cells. Chin J Cancer Research. Sept 2011; 23(3):208-‐13 Fujita T, Takeda Y, Sun HD, et al. Cytotoxic and antitumor activities of Rabdosia diterpenoids. Planta Med 1988; 54:414–417. Gao J-‐L, Shi J-‐M, He K, et al. Yanhusuo extract inhibits metastasis of breast cancer cells by modulating mitogen-‐activated protein kinase signaling pathways. Oncology reports. 2008, vol. 20, no4, pp. 819-‐824 Gao JL, Shi JM, He K, et al. Yanhusuo extract inhibits metastasis of breast cancer cells by modulating mitogen-‐activated protein kinase signaling pathways. Oncol Rep. 2008 Oct;20(4):819-‐24. Gao JL, He TC, Li YB, Wang YT. A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-‐tumor activity. Oncology Reports. 22:1077-‐83, 2009 Gao J, W. A. Morgan, A. Sanchez-‐Medina, and O. Corcoran, The ethanol extract of Scutellaria baicalensis and the active compounds induce cell cycle arrest and apoptosis including upregulation of p53 and Bax in human lung cancer cells. Toxicology and Applied Pharmacology, vol. 254, no. 3, pp. 221–228, 2011. Garg AK, Buchholz TA, & Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal, 2005 7(11-‐12), 1630-‐164 Gay LJ & Felding-‐Habermann B. Contribution of platelets to tumour metastasis. Nature Reviews Cancer. 2011 11, 123–134. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nature Reviews Cancer 14,430– 439 (2014) doi:10.1038/nrc3726 Gu G, Barone I, Gelsomino L, et al. Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERα/Sp1-‐mediated p53 activation. J Cell Physiol. 2012 Oct;227(10):3363-‐72. doi: 10.1002/j.24035. 247
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* * * * * *
*
Hämäläinen M, Nieminen R, Vuorela P, et al. Anti-‐Inflammatory Effects of Flavonoids: Genistein, Kaempferol, Quercetin, and Daidzein Inhibit STAT-‐1 and NF-‐κB Activations, Whereas Flavone, Isorhamnetin, Naringenin, and Pelargonidin Inhibit only NF-‐κB Activation along with Their Inhibitory Effect on iNOS Expression and NO Production in Activated Macrophages. Mediators of Inflammation. Volume 2007 http://dx.doi.org/10.1155/2007/45673 He Yh, Zheng X, Sit C, et al. Using association rules mining to explore pattern of Chinese medicinal formulae (prescription) in treating and preventing breast cancer recurrence and metastasis. Journal of Translational Medicine 2012, 10(Suppl 1):S12 doi: 10.1186/1479-‐5876-‐10-‐S1-‐S12 Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. Oridonin-‐-‐a new antitumor subject. Chin Science Bull 1978; 23:53–56. Holtkamp W, Nagel GA, Wander H-‐E, et al. Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. International Journal of Cancer. Volume 34, Issue 3, pages 323–328, 1 September 1984. DOI: 10.1002/ijc.2910340307 Hortobagyi GN, de la Garza Salazar J, Pritchard K, et al. ABREAST Investigators: The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 2005, 6:391-‐401. Hsiao WL, Liu L. The role of traditional Chinese herbal medicines in cancer therapy-‐-‐from TCM theory to mechanistic insights. Planta Med. 2010 Aug;76(11):1118-‐31. doi: 10.1055/s-‐0030-‐1250186. Hsu YL, Yen MH, Kuo PL, et al. San-‐Zhong-‐Kui-‐Jian-‐Tang, a traditional Chinese medicine prescription, inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis. Biol Pharm Bull. 2006; 29 2388-‐2394 Hu Yy, Chen X, Duan Hq, Hu Yl & Mu X. Pulsatilla decoction and its active ingredients inhibit secretion of NO, ET-‐1, TNF-‐, and IL-‐1 in LPS-‐induced rat intestinal microvascular endothelial cells. 2010 Cell Biochemistry and Function Cell Biochemistry and Function. Vol. 27 Issue 5, Pp. 284-‐8. DOI:10.1002/cbf.1570 Hu M, Lv GM, Chen RZ, et al. Treatment of Advanced Breast Cancer with Chinese Medicinal Herbs of Fei Decoction: A Case Report. Curr Pharm Biotechnol. 2014 Apr 8.
248
16/12/14
References * * * * * * * * * * * * *
Huang ZF, Wei JS, Li HZ, Tan ZO, Zhang ZJ, Chen C. Effect of Shenqi Fuzheng injection combined with chemotherapy on thirty patients with advanced breast cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008; 28 152-‐154 Huang MT, Smart RC, Wong C, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-‐O-‐tetradecanoylphorbol-‐13-‐acetate. Cancer Research Journal, 1988;48: 5941-‐5946 Huang Z, Chen G, Shi P. Emodin-‐induced apoptosis in human breast cancer BCap-‐37 cells through the mitochondrial signaling pathway. Archives of Pharmacal Research June 2008, Volume 31, Issue 6, pp 742-‐748 Huang PH, Huang CY, Chen MC, et al. Emodin and Aloe-‐Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition. Evid Based Complement Alternat Med. 2013;2013:376123. doi: 10.1155/2013/376123. Hwang JT, Park OJ, Lee YK, et al. Anti-‐tumor effect of luteolin is accompanied by AMP-‐activated protein kinase and nuclear factor-‐κB modulation in HepG2 hepatocarcinoma cells. International Journal of Molecular Medicine, Volume 28, Number 1, 2011, pp. 25-‐31(7) Im JH, Fu W, Wang H, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Research, 2004 64, 8613–8619 International Menopause Society.org http://www.imsociety.org/updates_view_open.php menopauseliveID=611&SESSID=jfovnf6ukbltcqŠ63iujd5 Jeong JY, Chung YB, Lee CC, Park SW, Lee CK. Studies on immunopotentiating activities of antitumour polysaccharide from aerial parts of Taraxacum platycarpum. Biological & Pharmaceutical Journal. 2009;22(6): 602-‐5 Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-‐kappaB signaling. Nutr Cancer. 2004;49(2):209-‐16. Jiang J, Slivova V, Sliva D. Ganoderma lucidum inhibits proliferation of human breast cancer cells by down-‐regulation of estrogen receptor and NF-‐κB signaling. International Journal of Oncology. 2006;29(3):695–703. Jiang WG, Ye L, Ji K, Frewer N, Ji J, Mason MD. Inhibitory effects of Yangzheng Xiaoji on angiogenesis and the role of the focal adhesion kinase pathway. Int J Oncol. 2012 Nov;41(5):1635-‐42. doi: 10.3892/ijo.2012.1627. Jiang et al. The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells. Journal of Experimental & Clinical Cancer Research 2012, 31:42 Jin D-‐Z, Yin L-‐L, Jia X-‐Q & Zhu X-‐Z. Cryptotanshinone inhibits cyclooxygenase-‐ 2 enzyme activity but not its expression. European 249 16/12/14 Journal of Pharmacology. Volume 549, Issues 1-‐3, 7 November 2006, Pp. 166-‐72. doi:10.1016/j.ejphar.2006.07.055
References * * * * * * * * * * *
*
Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-‐regulation of interferon-‐β and TNF-‐α in human breast cancer cells. Carcinogenesis, 26(11):1934-‐1939. doi:10.1093/carcin/bgi154 Kassi E, Sourlingas TG, Spiliotaki M, et al. Ursolic acid triggers apoptosis and Bcl-‐2 downregulation in MCF-‐7 breast cancer cells. Cancer Investigation, 27 (2009), pp. 723–733 Kim SH, Lee SE, Oh H, et al. Am J Chin Med. 2002;30(1):127-‐37. Kim JB, Lee K-‐M, Ko E, et al. Berberine Inhibits Growth of the Breast Cancer Cell Lines MCF-‐7 and MDA-‐MB-‐231. Planta Med 2008; 74(1): 39-‐42. DOI: 10.1055/s-‐2007-‐993779 Kim AD, K. A. Kang, R. Zhang et al. Ginseng saponin metabolite induces apoptosis in MCF-‐7 breast cancer cells through the modulation of AMP-‐activated protein kinase. Environmental Toxicology and Pharmacology, vol. 30, no. 2, pp. 134–140, 2010. Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell-‐cycle arrest. Phytomedicine, 17(6):436-‐40. doi: 10.1016/j.phymed.2009.08.012. Kim JB, Yu JH, Ko E, Lee KW, et al. The alkaloid Berberine inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell cycle arrest. Phytomedicine. 2010 May;17(6):436-‐40. doi: 10.1016/j.phymed.2009.08.012. Kim KH, H.S. HS, Choi HS, et al. Induction of apoptotic cell death by ursolic acid through mitochondrial death pathway and extrinsic death receptor pathway in MDA-‐MB-‐231 cells. Archives of Pharmacal Research, 34 (2011), pp. 1363–1372 King ML, Adler SR, Murphy LL. Extraction-‐dependent effects of American ginseng (Panax quinquefolium) on human breast cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther. 2006 Sep;5(3):236-‐43 King ML, Murphy LL. American ginseng (Panax quinquefolius L.) extract alters mitogen-‐activated protein kinase cell signaling and inhibits proliferation of MCF-‐7 cells. J Exp Ther Oncol. 2007;6(2):147-‐55. Kinouchi FL, Maia DC, de Abreu Ribeiro LC, et al. A soy-‐based product fermented by Enterococcus faecium and Lactobacillus helveticus inhibits the development of murine breast adenocarcinoma. Food Chem Toxicol. 2012 Nov;50(11):4144-‐8. doi: 10.1016/ j.fct.2012.08.038. Kopp HG, Placke T & Salih HR. Platelet-‐derived transforming growth factor-‐beta down-‐regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Research 2009 69, 7775–7783. 250
16/12/14
References * * * * * * * *
*
*
Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011;121(10):3804–3809. doi:10.1172/JCI57099. Kumar RA, Sridevi K, Kumar NV, Nanduri S, Rajagopal S. Anticancer and immunostimulatory compounds from Andrographis paniculata. Journal of Ethnopharmacology. 2004 92(2-‐3): 291-‐295. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med 2000, 248:171-‐183. Labelle M, Begum S & Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-‐mesenchymal-‐like transition and promotes metastasis. Cancer Cell. 2011 20, 576–590. Lai J-‐N, Wu C-‐T, Wang J-‐D. Prescription Pattern of Chinese Herbal Products for Breast Cancer in Taiwan: A Population-‐Based Study. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/891893 Lee E, Levine EA, Franco VI, et al. Combined Genetic and Nutritional Risk Models of Triple Negative Breast Cancer. Nutrition and Cancer. 2014 66:6, 955-‐963, DOI: 10.1080/01635581.2014.932397 Leitman DC, Christians U. MF101: a multi-‐component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs. 2012 Jul;21(7):1031-‐42. doi: 10.1517/13543784.2012.685652. Li Y, Fan L, Sun Y, Miao X, et al. Paris saponin VII from trillium tschonoskii reverses multidrug resistance of adriamycin-‐resistant MCF-‐7/ADR cells via P-‐glycoprotein inhibition and apoptosis augmentation. J Ethnopharmacol. 2014 Jul 3;154(3):728-‐34. doi: 10.1016/j.jep.2014.04.049. Li JW, Liu XF, Chen HZ, Chen HH, Shi GX, Wang SJ. [Effect of yanghe huayan decoction on precancerosis of breast cancer, protein and mRNA expression of ki67: an experimental research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Aug;34(8):970-‐5. [Article in Chinese] Liao F. Herbs of activating blood circulation to remove blood stasis. Clinical Hemorheology and Microcirculation. Volume 23, Numbers 2-‐4/2000
251
16/12/14
References * * * * * *
* * *
*
Lai J-‐N, Wu C-‐T, Wang J-‐D. Prescription Pattern of Chinese Herbal Products for Breast Cancer in Taiwan: A Population-‐Based Study. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/891893 Lecumberri E, Dupertuis YM, Miralbell R, Pichard C. Green tea polyphenol epigallocatechin-‐3-‐gallate (EGCG) as adjuvant in cancer therapy. Clinical Nutrition. Volume 32, Issue 6, December 2013, Pages 894–903 Lee SJ, K. Park, S. D. Ha, W. J. Kim, and S. K. Moon. Gleditsia sinensis thorn extract inhibits human colon cancer cells: the role of ERK1/2, G2/M-‐phase cell cycle arrest and p53 expression. Phytotherapy Research, vol. 24, no. 12, pp. 1870–1876, 2010. Leitman DC, Christians U. MF101: a multi-‐component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs. 2012 Jul;21(7):1031-‐42. doi: 10.1517/13543784.2012.685652. Li-‐Weber M. Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Letters. Volume 332, Issue 2 , Pages 304-‐312, 28 May 2013. doi:10.1016/j.canlet.2010.07.015 Li Y, Fan L, Sun Y, Miao X, et al. Paris saponin VII from trillium tschonoskii reverses multidrug resistance of adriamycin-‐resistant MCF-‐7/ADR cells via P-‐glycoprotein inhibition and apoptosis augmentation. J Ethnopharmacol. 2014 Jul 3;154(3):728-‐34. doi: 10.1016/j.jep.2014.04.049. Liao F. Herbs of activating blood circulation to remove blood stasis. Clinical Hemorheology and Microcirculation. Volume 23, Numbers 2-‐4/2000 Lin Y, et al. Breast Cancer Stages in TCM. [in Chinese] JCIM Journal 2006 Vol.4, No.5 DOI: 10.3736/jcim20060502 Lin Y-‐s, Tsai P-‐h, Kandaswami CC, et al. Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial– mesenchymal transition in A431 epidermal cancer cells. Cancer Science. Volume 102, Issue 10, pages 1829–1839, October 2011 DOI: 10.1111/j.1349-‐7006.2011.02035.x Lin C-‐H, Shen Y-‐A, Hung P-‐H, et al. Epigallocathechin gallate, polyphenol present in green tea, inhibits stem-‐like characteristics and epithelial-‐mesenchymal transition in nasopharyngeal cancer cell lines BMC Complementary and Alternative Medicine 2012, 12:201 doi:10.1186/1472-‐6882-‐12-‐201
16/12/14
References *
* *
* * * * * * * *
Lissoni P, Malugani F, Bonfanti A, Bucovec R, et al. Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-‐12 and endothelin-‐1. Journal of Biological Regulators and Homeostatic Agents 2001, 15(2):140-‐144 Liu H, Zang C, Emde A, et al. Anti-‐tumor effect of honokiol alone and in combination with other anti-‐cancer agents in breast cancer. Eur J Pharmacol. 2008 Sep 4;591(1-‐3):43-‐51. doi: 10.1016/j.ejphar.2008.06.026. Liu Y, Yin H-‐J, Shi D-‐z, Chen K-‐j. Chinese Herb and Formulas for Promoting Blood Circulation and Removing Blood Stasis and Antiplatelet Therapies. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012), http://dx.doi.org/ 10.1155/2012/184503 Liu Y, Cao W, Zhang B, et al. The natural compound magnolol inhibits invasion and exhibits potential in human breast cancer therapy. Sci Rep. 2013 Nov 14;3:3098. doi: 10.1038/srep03098. Liu W, Xu J, Liu Y, et al. Anthocyanins potentiate the activity of trastuzumab in human epidermal growth factor receptor 2-‐positive breast cancer cells in vitro and in vivo. Mol Med Rep. 2014 Oct;10(4):1921-‐6. doi: 10.3892/mmr.2014.2414. Lu Y, Lu YX. Clinical application and pharmacology function of Shenqi fuzheng injection. Li Shi Zhen Medicine and material medica research 2006, 17(10):2083-‐2085. Liu Y-‐d, et al. The Influence of Baicalin on the level of Serum TNF-‐α, IL-‐6, IL-‐10 in Diet-‐induced Hyperlipidemic and n-‐infected Mice. Si Chuan Zhong Yi. 2006; 24(9): Pp.19-‐20. Lu Q, Zhang P, Zhang X, Chen J. Experimental study of the anti-‐cancer mechanism of tanshinone IIA against human breast cancer. Int J Mol Med. 2009 Dec;24(6):773-‐80. Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression JCB. 2012 Vol.196 no.4 395-‐406 doi: 10.1083/jcb.201102147 Malewicz B, Wang Z, Jiang C, et al. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis. 2006 Sep;27(9):1739-‐47. Marques M, Laflamme L, Benassou I, et al. Low levels of 3,3'-‐diindolylmethane activate estrogen receptor α and induce proliferation of breast cancer cells in the absence of estradiol. BMC Cancer. 2014 Jul 21;14(1):524. doi: 10.1186/1471-‐2407-‐14-‐524. 253
16/12/14
References * * * * * * * * * * * * *
*
Matsumoto H, Wada T, Fukunaga K, et al. Bax to Bcl-‐2 Ratio and Ki-‐67 Index are Useful Predictors of Neoadjuvant Chemoradiation Therapy in Bladder Cancer. Jpn. J. Clin. Oncol. (2004) 34 (3): 124-‐130. doi: 10.1093/jjco/hyh026 Matthews AK, S. A. Sellergren, D. Huo, M. List, and G. Fleming. Complementary and alternative medicine use among breast cancer survivors. Journal of Alternative and Complementary Medicine, vol. 13, no. 5, pp. 555–562, 2007. Mocellin S, Nitti D. TNF and cancer: the two sides of the coin. Front Biosci. 2008 Jan 1;13:2774-‐83. Morel A-‐P, Lièvre M, Thomas C, Hinkal G, Ansieau S, et al. Generation of Breast Cancer Stem Cells through Epithelial-‐Mesenchymal Transition. PLoS ONE. 2008 3(8): e2888. doi:10.1371/journal.pone.0002888 Mueck AO, Seeger H. Breast cancer: are estrogen metabolites carcinogenic? Climacteric 2007;10(Suppl2):62-‐5. http://www.ncbi.nlm.nih.gov/pubmed/17882675 Mukherjee AK, Basu S, Sarkar N, Ghosh AC. Advances in cancer therapy with plant based natural products. Curr Med Chem 2001, 8:1467-‐1486. NCI. http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2 Nicastro HL, Firestone GL, Bjeldanes LF. 3,3'-‐diindolylmethane rapidly and selectively inhibits hepatocyte growth factor/c-‐Met signaling in breast cancer cells. J Nutr Biochem. 2013 Nov;24(11):1882-‐8. doi: 10.1016/j.jnutbio.2013.05.004. Oh YC, Choi JG, Lee YS, Brice OO, et al. Corydalis alkaloid Tetrahydropalmatine inhibits pro-‐inflammatory mediators in lipopolysaccharide-‐stimulated THP-‐1 cells. J Med Food. 2010 Oct;13(5):1125-‐32. Oka H, Shiozaki H, Kobayashi K, et al. Expression of E-‐cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res. 1993 Apr 1;53(7):1696-‐701. Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013 Aug;22 Suppl 2:S66-‐72. doi: 10.1016/j.breast.2013.07.012. Pal S, Bhattacharjee A, Ali A, et al. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism. Journal of Inflammation. 2014, 11:23 doi:10.1186/1476-‐9255-‐11-‐23 http://www.journal-‐inflammation.com/content/11/1/23 Palumbo JS, Talmage KE, Massari JV, et al. (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer 16/12/14 cell-‐mediated elimination of tumor cells. Blood, 105, 178–185. 254
References * * * *
* * * * *
* * *
Palumbo JS, Talmage KE, Massari JV, et al. (2007) Tumor cell-‐associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-‐dependent and-‐independent mechanisms. Blood, 110, 133–141. Park JE, et al. Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive Human Tumor Stromal Fibroblasts. The Journal of Biological Chemistry, 274, Pp.36505-‐12. 1999 doi: 10.1074/jbc.274.51.36505 Park IJ, Kim MJ, Park OJ, et al. Cryptotanshinone induces ER stress-‐mediated apoptosis in HepG2 and MCF7 cells. Apoptosis. 2012 Mar;17(3):248-‐57. doi: 10.1007/s10495-‐011-‐0680-‐3. Patel DD, Bhatavdekar JM, Chikhlikar PR, et al. Node negative breast carcinoma: Hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. Journal of Surgical Oncology. Volume 62, Issue 2, pages 86–92, June 1996. DOI: 10.1002/(SICI)1096-‐9098(199606)62:2<86::AID-‐JSO3>3.0.CO;2-‐M Payandeh M, et al. P53 mutation compared with Ki67 marker in metastasis of breast cancer in western Iran. Journ Solid Tumors. 2014 DOI: 10.5430/jst.v4n3p4 Peppercorn J. Breast Cancer in Women Under 40. 2009 Oncology 23 (6) Perez AT, Arun B, Tripathy D, Tagliaferri MA, et al. A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer. Breast Cancer Res Treat. 2010 Feb;120(1):111-‐8. doi: 10.1007/s10549-‐009-‐0678-‐5. Perwez-‐Hussain S, & Harris CC. Inflammation and cancer: an ancient link with novel potentials. International Journal of Cancer, 2007 121(11), PP.2373–80. Peterson G, Barnes S. Genistein inhibition of the growth of human breast cancer cells: Independence from estrogen receptors and the multi-‐drug resistance gene. Biochemical and Biophysical Research Communications. Volume 179, Issue 1, 30 August 1991, Pages 661–667 Rachmut IH, Samuels N, Melnick SJ, Ramachandran C, et al. Immunomodulatory effects of the botanical compound LCS101: implications for cancer treatment. 2013 Onco Targets Ther, 6:437–445. doi: 10.2147/OTT.S42038 Rajagopal S, kumar SA, Dhanvanthri S. et al. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. Journal of Experimental Therapeutics and Oncology. Volume 3, Issue 3, pages 147–158, May 2003 Rajah TT, Du N, Drews N, Cohn R. Genistein in the presence of 17beta-‐estradiol inhibits proliferation of ERbeta breast cancer cells. Pharmacology. 2009;84(2):68-‐73. doi: 10.1159/000226123. 255 16/12/14
References * * * * * * * *
* * * *
Ren Ls & Zhang H. Studies on the Anti-‐tumour Action of Lignum Sappan. China Journal of Chinese Materia Medica. 1990;05 DOI： conk:ISSN:1001-‐5302.0.1990-‐05-‐030 Ren Z-‐H, Tong Y-‐H,Xu W, Ma J, Chen Y. Tanshinone II A attenuates inflammatory responses of rats with myocardial infarction by reducing M-‐1 expression. Phytomedicine. Volume 17, Issues 3–4, March 2010, Pages 212–218 Rogan EG and Cavalieri EL. (2011) Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants. In Oxidative Stress: Diagnostics, Prevention, and Therapy. Chapter 4. DOI: 10.1021/bk-‐2011-‐1083.ch004 Saunders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-‐term follow-‐up. Cancer. 2005;103:2481–2484. doi: 10.1002/cncr.21069. Shang X, Pan H, Li M, Miao X, Ding H. Lonicera japonica Thunb.: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. Journal of Ethnopharmacology. Volume 138, Issue 1, 31 October 2011, Pages 1–21 DOI: 10.1016/j.jep.2011.08.016 Shao J-‐w, Dong H-‐y, Wang T, Guo Y-‐h. Traditional Chinese medicine Rhizoma curcumae activates PXR and affects cytochrome P450 3A in the rat liver. Zhong Guo Yao Li Xue Tong Bao. 2008, 24(4): 504-‐509 Shi J, et al. Characterization of Aromatase Binding Agents from the Dichloromethane Extract of Corydalis yanhusuo Using Ultrafiltration and Liquid Chromatography Tandem Mass SpectrometryMolecules 2010, 15, 3556-‐3566; doi:10.3390/ molecules15053556 Schonthal AH. Targeting endoplasmic reticulum stress for cancer therapy. Front Biosci (Schol Ed). 2012 Jan 1;4:412-‐31.Schulz M, Hoffmann K, Weikert C, et al. Identification of a dietary pattern characterized by high-‐fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-‐Potsdam Study. Br J Nutr 2008, 100:942-‐946. Serafim TL, F. S. Carvalho, M. P. M. Marques et al. Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. Chemical Research in Toxicology, vol. 24, no. 5, pp. 763–774, 2011. Setchell KDR, Borriello SP, Hulme P, Kirk DN, Axelson M. Nonsteroidal estrogens of dietary origin: possible roles in hormone-‐ dependent disease. Am J Clin Nutr. 1984;40:569–78. Shao Sj, Wu Xq, Feng J, et al. Effect of Ru’ai Shuhou Recipe on HER2 signal transduction pathway and related matrix proteins during the process of recurrence and metastasis of HER2 over-‐expression in rats with breast cancer. Shang Hai Zhong Yi Yao Za Zhi. 2013, 47(6): 89-‐92. 16/12/14 Sotoca AM, Ratman D, van der Saag P, et al. Phytoestrogen-‐mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ERalpha/ERbeta ratio. J Steroid Biochem Mol Biol. 2008 Dec;112(4-‐5):171-‐8. doi: 10.1016/j.jsbmb.2008.10.002.
References * * * * * * * * * * * * * * *
Stark A, Madar Z. (2002). Phytoestrogens: a review of recent findings. J Pediatr Endocrinol Metab, 15(5):561-‐72. Stewart CA, Vivier E & Colonna M. Strategies of natural killer cell recognition and signaling. Current Topics in Microbiology and Immunology. 2006 298, 1–21. Stovall DW, Pinkerton JV. MF-‐101, an estrogen receptor beta agonist for the treatment of vasomotor symptoms in peri-‐ and postmenopausal women. Curr Opin Investig Drugs. 2009 Apr;10(4):365-‐71. Suganuma M, Okabe S, Kurusu M, et al. Discrete roles of cytokines, TNF-‐alpha, IL-‐1, IL-‐6 in tumor promotion and cell transformation. Int J Oncol. 2002 Jan;20(1):131-‐6. Sun DZ, Xu L, Wei PK, Liu L, He J. Syndrome differentiation in traditional Chinese medicine and E-‐cadherin/ICAM-‐1 gene protein expression in gastric carcinoma. World J Gastroenterol. 2007 Aug 28;13(32):4321-‐7. Tang W, Eisenbrand G. Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Berlin: Springer-‐Verlag. 1992:817–847. Tao J, Zhang P, Liu G, et al. Cytotoxicity of Chinese motherwort (YiMuCao) aqueous ethanol extract is non-‐apoptotic and estrogen receptor independent on human breast cancer cells. J Ethnopharmacol. 2009 Mar 18;122(2):234-‐9. Tsai YT, Lai JN, Wu CT. The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: A population-‐based study. J Ethnopharmacol. 2014 Sep 11;155(2):1256-‐62. doi: 10.1016/j.jep.2014.07.008. Ursin G, London S, Stanczyk FZ, et al. A pilot study of urinary estrogen metabolites (16alpha-‐OHE1 and 2-‐OHE1) in postmenopausal women with and without breast cancer. Environ Health Perspect. 1997 Apr;105 Suppl 3:601-‐5. van Dijk M, Göransson SA, Strömblad S. Cell to extracellular matrix interactions and their reciprocal nature in cancer. Experimental Cell Research. Volume 319, Issue 11, 1 July 2013, Pages 1663–1670 Virk-‐Baker MK, Nagy TR, Barnes S. (2010) Role of phytoestrogens in cancer therapy. Planta Med. 2010 Aug;76(11):1132-‐42. doi: 10.1055/ s-‐0030-‐1250074. Vitale DC. Piazza, C, Melilli B, Drago F, Salomone S. (2013) Isoflavones: estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet. 2013 Mar;38(1):15-‐25. Vivar OI, Saunier EF, Leitman DC, et al. Selective activation of estrogen receptor-‐beta target genes by 3,3'-‐diindolylmethane. Endocrinology. 2010 Vol. 151, No. 4 Pp. 1662-‐7. doi:10.1210/en.2009-‐1028 Wang SC, Zhang L, Hortobagyi GN, Hung MC. Targeting HER2: recent developments and future directions for breast cancer patients. Semin Oncol. 2001 Dec;28(6 Suppl 18):21-‐9. 257 16/12/14 Wang Sm, et al. Nan Hua Da Xue Xue Bao [Chinese language medical edition]. 2007; 35(1): 4-‐6.
References * * * * * * * * * * * * * *
Wang Z-‐Y, Wang D-‐M, Loo TY, et al. Spatholobus suberectus inhibits cancer cell growth by inducing apoptosis and arresting cell cycle at G2/M checkpoint. Journal of Ethnopharmacology. Volume 133, Issue 2, 27 January 2011, Pages 751–758 Wang J, Xiao X, Zhang Y, et al. Simultaneous modulation of COX-‐2, p300, Akt, and Apaf-‐1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res. 2012 Aug;53(1):77-‐90. doi: 10.1111/j.1600-‐079X.2012.00973.x. Wang J-‐s, Ren T-‐n, Xi T. Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-‐7 human breast cancer cells. Medical Oncology. March 2012, Volume 29, Issue 1, pp 10-‐15 Wang J, Wang Q, Li L, Li Y, et al. Phlegm-‐dampness constitution: genomics, susceptibility, adjustment and treatment with traditional Chinese medicine. Am J Chin Med. 2013;41(2):253-‐62. doi: 10.1142/S0192415X13500183. Wang X, Chen YG, Ma L, et al. Effect of Chinese medical herbs-‐Huiru Yizeng Yihao on hyperprolactinemia and hyperplasia of mammary gland in mice. Afr J Tradit Complement Altern Med. 2013 May 16;10(4):24-‐35. Wang D, Lu J, Liu Y, et al. Liquiritigenin induces tumor cell death through mitogen-‐activated protein kinase-‐ (MPAKs-‐) mediated pathway in hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:965316. doi: 10.1155/2014/965316. Way T-‐D, Kao M-‐C, Lin J-‐K, et al. Apigenin Induces Apoptosis through Proteasomal Degradation of HER2/neu in HER2/neu-‐ overexpressing Breast Cancer Cells via the Phosphatidylinositol 3-‐Kinase/Akt-‐dependent Pathway. 2004 The Journal of Biological Chemistry, 279, 4479-‐4489. doi: 10.1074/jbc.M305529200 Wicha, M. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. Journal of Clinical Investigation, Vol. 120, No. 2, February 2010; doi:10.1172/JCI39397 Wong KC, Wu L-‐T. History of Chinese Medicine. Tientsin, China: The Tientsin Press 1932 Woo JH, Li D, Wilsbach K, et al. Coix seed extract, a commonly used treatment for cancer in China, inhibits NFkappaB and protein kinase C signaling. Cancer Biol. Ther 2007; 6: 2005–2011 Xian, L. & Qian, S-‐h. Progress in the Studies of Anti-‐cancer Function of Traditional Chinese Medicines. Chinese Wild Plant Resources. 2009;04. DOI: CNKI:SUN:ZYSZ.0.2009-‐04-‐000 Xiao, F-‐y., et al. Zhong Guo Zhong Yao Za Zhi. 2005; 30(22): PP.1763-‐66. Xu Yy, Zhang Y, Zhou F, et al. Human pregnane X receptor-‐mediated transcriptional regulation of CYP3A4 by extracts of 7 traditional Chinese medicines. Zhong Guo Zhong Yao Za Zhi. 2011, 36(11): 1524-‐1527. Xue D, Sun H, Li PP. Long-‐term Chinese herbs decoction istration for management of hot flashes associated with endocrine therapy in breast cancer patients. Chin J Cancer Res. 2011 Mar;23(1):74-‐8. doi: 10.1007/s11670-‐011-‐0074-‐7. 258
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Yaacob NS, Hamzah N, Nik Mohamed Kamal NN, et al. Anticancer activity of a sub-‐fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro. BMC Complement Altern Med. 2010 Aug 5;10:42. doi: 10.1186/1472-‐6882-‐10-‐42. Yaacob NS, Kamal NN, Norazmi MN. Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-‐7 and MDA-‐MB-‐231 human breast cancer cell lines. BMC Complement Altern Med. 2014 Jul 18;14(1):252. doi: 10.1186/1472-‐6882-‐14-‐252. Yan YY, Zheng LS, Zhang X, et al. Blockade of Her2/neu binding to Hsp90 by emodin azide methyl anthraquinone derivative induces proteasomal degradation of Her2/neu. Mol Pharm. 2011 Oct 3;8(5):1687-‐97. doi: 10.1021/mp2000499. Yang LR, Xu XY. Clinical application and curative effect evaluation of Shenqi fuzheng injection. Heilongjiang Journal of Traditional Chinese Medicine 2004, 4:46-‐48. Yang L, Li L, Chen Y, Parkin DM. Cancer Incidence and Mortality Estimates and Prediction for year 2000 and 2005 in China. Chinese Journal of Health Statistics 2005, 22:218-‐222. Yang Xf, Liao Mc, Yang Zm, et al. Effect of Panax notoginseng on genes expression of CYP and GST in lung tissues of rats. Zhong Guo Zhong Yao Za Zhi. 2009, (17): 2236-‐2240. Yang Y-‐F, Liao J. Exploration of Key Points in Evaluation Criteria of Chinese Medicine in the Treatment of Cancer. Chin J Integr Med 2010 Feb;16(1):3-‐5 Ye L, Ji K, Frewer N, Ji J, Jiang WG. Impact of Yangzheng Xiaoji on the adhesion and migration of human cancer cells: the role of the AKT signalling pathway. Anticancer Res. 2012 Jul;32(7):2537-‐43. Yeh C-‐T, Wu C-‐H, Yen G-‐C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-‐Jun N-‐terminal kinase, Akt and mammalian target of rapamycin signaling. Molecular Nutrition & Food Research. Volume 54, Issue 9, pages 1285–1295, September 2010 DOI: 10.1002/mnfr.200900414 Yin Y, Shi R, Shen H-‐M. Luteolin, a flavonoid with potentials for cancer prevention and therapy. Curr Cancer Drug Targets. Nov 2008; 8(7):634-‐48 Yuko Izuhara Y, Takahashi S, Nangaku M, et al.Inhibition of Plasminogen Activator Inhibitor-‐1; Its Mechanism and Effectiveness on Coagulation and Fibrosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008; 28: 672-‐677, doi: 10.1161/ATVBAHA. 107.157479 Zhang L, Chang C-‐j,Bacus SS, Hung M-‐C. Suppressed Transformation and Induced Differentiation of HER-‐2/neu-‐overexpressing Breast Cancer Cells by Emodin. Cancer Res September 1, 1995 55; 3890 259 16/12/14
References *
* * * * * * * * * * *
Zhang L, Lau Y-‐K, Xia W, Hortobagyi GN, Hung M-‐C. Tyrosine Kinase Inhibitor Emodin Suppresses Growth of HER-‐2/neu-‐ overexpressing Breast Cancer Cells in Athymic Mice and Sensitizes These Cells to the Inhibitory Effect of Paclitaxel. Clin Cancer Res February 1999 5; 343 Zhang, S-‐p., et al. Tian Jin Zhong Yi. [Chinese language medical edition] 2000; 17(2):Pp. 34-‐5. Zhang, K-‐f., et al. Zun Yi Yi Xue Yuan Xue Bao. [Chinese language medical edition] 2004; 27(2):Pp. 134-‐6. Zhang YX, Chen Y, Guo XN, et al. 11,11'-‐dideoxy-‐verticillin: a natural compound possessing growth factor receptor tyrosine kinase-‐ inhibitory effect with anti-‐tumor activity. Anticancer Drugs. 2005 Jun;16(5):515-‐24. Zhang Y, Li P-‐P. Shu-‐Gan-‐Liang-‐Xue Decoction, a Chinese herbal formula, down-‐regulates the expression of steroid sulfatase genes in human breast carcinoma MCF-‐7 cells. Journal of Ethnopharmacology 127 (2010) 620–624 Zhang J, Zhan Z, Wu J, Zhang C, et al. Relationship between EGF, TGFA, and EGFR Gene Polymorphisms and Traditional Chinese Medicine ZHENG in Gastric Cancer. Evid Based Complement Alternat Med. 2013;2013:731071. doi: 10.1155/2013/731071. Zhao C, Yin S, Dong Y, et al. Autophagy-‐dependent EIF2AK3 activation compromises ursolic acid-‐induced apoptosis through upregulation of MCL1 in MCF-‐7 human breast cancer cells. Autophagy. 2013 Feb 1;9(2):196-‐207. doi: 10.4161/auto.22805. Zhong ZH. Dictate history: A national new medicine that come from experiential prescription. Journal of China Prescription Drug 2009, 1(82):33-‐36. Zhou Z-‐T & Zhang W-‐X. Effects of two Chinese herbs on proliferation during oral carcinogenesis. 2005 Oral abstract The IADR/ AADR/CADR 83rd General Session Zhou G-‐B, Chen S-‐J, Wang Z-‐Y, Chen Z. Back to the future of oridonin: again, compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo. Cell Research (2007) 17: 274–276. doi: 10.1038/cr.2007.21 Zhou Q-‐m, Wang S, Zhang H, et al. The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells. Acta Pharmacologica Sinica (2009) 30: 1648–1658; doi: 10.1038/aps.2009.166 Zhou N, Han, S-‐Y, Zhou F, Li P-‐p. Anti-‐tumor effect of Shu-‐gan-‐Liang-‐Xue decoction in breast cancer is related to the inhibition of aromatase and steroid sulfatase expression. Journal of Ethnopharmacology. Volume 154, Issue 3, 3 July 2014, Pages 687–695 260
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Protects normal cells and tissues against damage caused by chemo or radiotherapy
Prolongs life span and QoL in late stage cancer
Enhances the potency of chemo and radiotherapy
TCM as a Complementary Therapy for Cancer
Improves quality of life, physically and mentally. Allows patients to feel some control
Improves general condition and fatigue, increases body resistance [email protected]
Reduces inflammation and reduces or stops angiogenesis
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MeSH Search & Databases * ("breast neoplasms"[MeSH ] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]) AND herbs[All Fields] This search provided 132 articles * ("breast neoplasms"[MeSH ] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]) AND supplements[All Fields] produced 806 articles * Traditional Chinese Medicine Information Database: http://tcm.cz3.nus.edu.sg/group/tcm-‐id/tcmid_ns.asp. 16/12/14 http://www.megabionet.org/tcmid/
Bio-‐Active • Most modern medicines clinically available for cancer treatments are expensive and known for their toxicity and serious adverse reactions. • It is important to provide scientific evidence for the benefit of bioactive constituents used in ancient systems of medicine and identify novel compounds/ molecules from natural sources 4 (Swaroop et al., 2014).
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CM & Cancer * According to the theory of Chinese medicine (CM), the evaluation of how to treat cancer with CM is a criterion of whether the patient's subjective symptoms are being improved or not, which cannot necessarily be proven by Western medicine (WM). * On the one hand, almost all cancer patients in China would turn to CM treatment; on the other hand, valid evidences in the CM field cannot be offered to convince specialists in the WM field, and the effectiveness of CM cannot be explained either (Yang & Liao, 2010).
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CM & Cancer * Before a uniform curative effect evaluation standard comes out and is accepted, the up-‐to-‐date indices like disease control rate (DCR), time-‐to-‐progression (TTP), Karnofsky performance score (KPS) , body weight, and relevant main symptoms of disease could be used as short-‐term standards. * While indexes of progression-‐free survival (PFS), time-‐to-‐ progression (TTP), disease-‐free survival (DFS), overall survival (OS) could be used as long-‐term standards. Such methods could both represent the advantages of CM, and be accepted by WM (Yang & Liao, 2010).
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Breast Cancer * Every year, among the 1.2 million women diagnosed with breast cancer worldwide, 500 thousand cases die of the disease. Along with a sharp increase in life expectancy, expansion of urbanisation and adaptation of western lifestyle, the increase in incidence rates is even more obvious in developing countries (Hortobagyi et al, 2005; Schulz et al, 2008). * In China, the number of cases increased by 38.5% from 2000 to 2005. Compared with the early surveys in the 1990s, breast cancer ed for the largest increase in mortality rates in 2005 (Yang et al, 2005). * In 2009, breast cancer was the most common cancer in Australian women, ing for 27.4 per cent of all new cancers in women, with the average age of 60.7 years and with the risk of 1 in 8 women 7 16/12/14 before 85 year old
Breast Cancers * Between 65 to 75 per cent of breast cancers are hormone receptor-‐positive. * About 15 to 20 per cent of all breast cancers are HER2+ * About 15-‐20 per cent of all breast cancers in the U.S. are TNBC. * BRCA1 and BRCA2 mutations for about 20 to 25 per cent of hereditary breast cancers and about 5 to 10 per cent of all breast cancers. * 5 per cent are metastatic when discovered * 20% to 30% of patients with early breast cancers will experience relapse with distant metastatic disease [email protected]
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Breast Cancer * There is a 10% to 30% chance of recurrence and metastasis after treatment. Among the patients with local recurrence, 75% to 93% will eventually develop distant metastasis with an extremely low 5-‐year survival rate. * Chinese medicine adopts an overall therapeutic approach to treat and prevent recurrence and metastasis, to improve the immune system of patients, and to strengthen the body’s susceptibility to diseases. Meanwhile, Chinese medicine also aims at reducing the side effects of radiotherapy and chemotherapy, reversing drug resistance and improving quality of life and survival for patients (Mukherjee et al, 2001; Hsiao et al., 2010). [email protected]
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Breast Cancer & TCM * Inspecting the history of drug development during the past half century demonstrates that natural resources represent a significant segment on the pharmaceutical market compared to randomly synthesised compounds. As compiled by the World Health Organization, more than 21,000 plant species have been used worldwide in herbal medicines. * Herbs are an important source for drug development. The traditional Chinese medicine (TCM) has held and still holds an important position in primary health care in China and has been recently recognised by Western countries as a fertile source for revealing novel lead molecules for modern drug discovery (Li-‐Weber 2013). [email protected]
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PubMed database from 1960 to 2013 * Since a tremendous interest in acupuncture and herbal medicine was observed in 2000, the increasing numbers of published papers per year are apparent. In 2013, more than 90 papers on acupuncture and more than 450 papers on herbal medicines appeared in the area of cancer prevention and therapy. Survey of literature deposited in the PubMed database from 1960 to 2013 with the keywords (a) “acupuncture” or “herbal” and (b) “acupuncture and cancer” or “herbal and cancer.” [email protected]
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Cancer * The first mention of cancer was in the Song Dynasty (ca. 1300 AD).The Chinese word Ai (癌) meaning malignant carcinoma – first appeared in the ancient medical book “Wei Ji Bao Shu” (衛 濟寶書). According to the theories of TCM, cancer is caused by imbalances between endogenous physical conditions of the body and exogenous pathogenic factors. * The internal condition of the body plays a dominant role in the onset of cancer. In other words, factors can induce cancer only when the body's own defence system fails. * Those pathogenic factors, in Chinese medicine , include accumulated ‘Toxins’, ‘Heat and Blood Stasis’, and they attack when a person is in a weak physical condition, without the 16/12/14 strength to resist (Hsiao & Liu, 212 010).
TCM & Breast Cancer * Traditional Chinese medicine (TCM) may serve as a useful model for scientific inquiry since there is a standardised system of diagnostics and therapies, and this discipline is practiced worldwide. Among the components of TCM, herbal or botanical agents possess complex biological activities that could affect many aspects of carcinogenesis such as cell growth and proliferation, apoptosis, host-‐tumour interactions, and immune function and differentiation (Hsiao & Liu, 2010). * The theory of TCM coupled with laboratory studies and safety information can serve as a basis for the design of more definitive trials of TCM for specific indications in breast cancer (Cohen et al., 2002). [email protected]
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Patterns in Chinese medicine * A common causative pattern is that excessive ‘Heat’ from a deficient ‘Liver’, combined with ‘Phlegm Dampness’ due to ‘Spleen’ dysfunction, results in the blockage of qi and ‘Blood’, which then "condenses" into breast cancer. * Another common causative pattern is when ‘Liver’ Deficiency and ‘Kidney’ Deficiency lead to qi and ‘Blood’ Deficiency. Chronic qi and ‘Blood’ deficiency then leads to qi ‘Stagnation’ and ‘Blood Stasis’, which causes the formation of lumps in the breast (He et al, 2012).
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Patterns in Chinese medicine * A third pattern is when qi ‘Stagnation’ and ‘Phlegm’ accumulation lead to excessive ‘Heat Toxins’, which then turn to hard breast lump masses. * Traditionally, four patterns of breast cancer are differentiated for treatment: ‘Liver qi Stagnation’ (hard masses without pain and redness); ‘Phlegm Heat Obstruction’ (hard masses with sharp pain and redness and swelling); ‘Liver/Kidney Deficiency’ (hard lumps with swelling and a dimpled appearance of the breast skin, discharges and indentation of the nipple); ‘qi/Blood Deficiency’ (hard lumps with swelling, ruptured abscesses, spreading to the surrounding areas). [email protected]
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Patterns DCIS * Traditional Chinese Medicine (TCM) differential diagnoses for patient with ductal carcinoma in situ (DCIS). * Bars represent the frequency with which various TCM diagnoses were given preceding treatment. There are nine instances of spleen qi deficiency, either alone (seven instances) or as heart blood and spleen qi deficiency (two instances) (Dehen, 2013).
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Breast Cancer & CHM * The reported incidence of use of complementary and alternative medicines (CAMs) among women with breast cancer ranges from 66.7 to 97% (Matthews et al., 2007; Chen et al. 2008) * Traditional Chinese medicine (TCM) has been growing in popularity and has offered an important alternative or complement to health care in many countries. The most common type of CAM used by Chinese women with breast cancer is Chinese herbal medicine. * The majority of patients reported that they had benefited from the use of CHM (Cui et al., 2004).
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Breast Cancer & CHM * Previous studies have disclosed the potential beneficial synergistic effects of the usage of Radix Angelica sinensis (Serafim et al., 2011) or Radix Panax ginseng (Kim et al., 2010) among women with breast cancer. Jia Wei Xiao Yao San (Augmented Rambling Powder) was the most frequently prescribed formula (Lai et al., 2012). * A previous four-‐year survey by Cui et al., (2004) indicated that over 50% of breast cancer patients considered CHP effective in treating cancer.
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Breast Cancer & CHM * Results suggest that, under the coexistence of the conventional medical treatments and TCM, most breast cancer patients consumed herbal therapies with the intention of relieving their treatment-‐induced symptoms, rather than rejecting standard cancer treatments (Lai, Wu, Wang, 2012). * Patients who were younger, married, had higher education or income, received chemotherapy or radiotherapy, or had recurrence/metastasis of cancer tended to use CHM more frequently than other patients.
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Breast Cancer & CHM * From the herbal perspective, breast cancer is the local manifestation of a whole-‐body disease, referred to as an intrinsically deficient but extrinsically excessive syndrome. * Based on TCM theories, deficiency of ‘Spleen qi’, inadequate source of engendering transformation, deficiency of qi and ‘Blood’, and excess of ‘Phlegm-‐Dampness’ are believed to be the main mechanism responsible for development of breast cancer. * The recurrence and metastasis of breast cancer is considered to have a close relationship with ‘Liver dysfunctions’. These prescriptions focus on the herbs for nourishing the ‘yin-‐Blood’, and emolliating and regulating the ‘Liver’. Strengthening of ‘Liver’ function seems to be the key to successful treatment 20 16/12/14 (Chen et al., 2011).
Breast Cancer & the Microenvironment * Many tumours, including breast cancer, are maintained by a subpopulation of cells that display stem cell properties, mediate metastasis, and contribute to treatment resistance. * These cancer stem cells (CSCs) are regulated by complex interactions with the components of the tumour microenvironment — including mesenchymal stem cells, adipocytes, tumour associated fibroblasts, endothelial cells, and immune cells — through networks of cytokines and growth factors. * There is now overwhelming evidence that the behaviour of tumourigenic cells is also highly influenced by their microenvironment (Korkaya, Liu, Wicha, 2011). [email protected]
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Elevated levels of cytokines and growth factors produced by tumour cells enhance the proliferation and survival of CSCs, induce angiogenesis, and recruit tumour-‐associated macrophages, neutrophils, and mast cells, which secrete additional growth factors, forming a positive loop that promotes tumour cell invasion and metastasis. Metastatic Tumour
doi:10.1172/JCI57099
Non-‐metastatic Tumour
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Cytokines secreted by cells in the tumour microenvironment regulate BCSC self renewal. Tumour-‐associated fibroblasts (TAFs) and macrophages (TAMs) and MSCs have been shown to secrete IL-‐6, IL-‐8, and CXCL7, which in turn activate Stat3/NF-‐κB signalling, leading to self renewal of BCSCs. This generates a positive loop between the tumour microenvironment and tumor cells. doi:10.1172/JCI57099
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Isolates, Herbs and Formulas
Treatments
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The altered protein molecules upon treatments of TCM h25 erbal medicines and the associated cellular signalling networks. [email protected]
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Network Pharmacology Approach for CHM Research. * For the discovery of CHM-‐derived targets, effect prediction, mechanism clarification, and new drug assistant discovery using network pharmacology approach. It analyzes the information from public data, high-‐throughput experimental data, and TCM data and constructs a “CHM-‐TCM syndrome disease” interaction network using technologies of network expansion, optimisation, comparison, knockout, and addition. Finally, it carries out computational and experimental verifications. 26 16/12/14 doi: 10.1155/2013/621423
Triple Negative Breast Cancer
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TNBC * Triple-‐nega+ve breast cancer (TNBCa) (oestrogen receptor nega+ve, progesterone receptor nega+ve and human epidermal growth factor receptor 2 (Her2) nega+ve s for 10 to 17 per cent of all breast cancers . * They tend to be more aggressive than other types of breast cancer and have poor prognosis. The cause of death of pa+ents with TNBC is oFen recurrence (30-‐40% of cases), which presents as distant metastasis. * Unfortunately, the an+-‐tumour efficacy of commonly used chemotherapeu+c agents for TNBC, including pla+num-‐based chemotherapy, is limited due to acquired drug resistance and toxici+es. [email protected]
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TNBC * Triple negative breast cancer (TNBC) presents clinical challenges due to unknown aetiology, lack of treatment targets, and poor prognosis. Lee et al., (2014) examined combined genetic and nutritional risk models of TNBC in 354 breast cancer cases. * Results suggest that TNBC was associated with 6 DNA-‐repair non-‐synonymous single nucleotide polymorphisms (nsSNPs); ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6 G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W (rs1799782), and XPC A499V (rs2228000) and/or deficiencies in 3 micronutrients (zinc, folate, and b-‐carotene). [email protected]
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TNBC * Betulinic Acid (BetA), a pentacyclic triterpene discovered in 1995 from the stem bark of the plant Zizyphus mauri-ana, was ini+ally reported to be a melanoma-‐specific cytotoxic agent . Since then, BetA has been found to exhibit a variety of biological and medicinal proper+es such as an+-‐bacterial, an+-‐ malarial, an+-‐inflammatory and an+-‐cancer ac+vi+es * Weber et al (2014) inves+gated the cytotoxic effect of BetA on breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines. Furthermore, the an+-‐inflammatory and an+-‐angiogenic poten+al of BetA was also examined.
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BetA * Possible molecular mechanisms by which BetA induces cell cycle arrest in breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines, BetA treated cells were analysed for their DNA content by propidium iodide staining. * The data suggest that BetA treatment of MDA-‐MB-‐231 cell line could lead to the inhibi+on of DNA synthesis causing the arrest of cells in the G2 phase, eventually restraining the prolifera+on of cells. * The treatment of MDA-‐MB-‐231 cell line with 1 and 10µg/mL BetA lowered the expression of P21, P27, CDK2, CDK6 and Cyclin Dl whereas 20µg/mL BetA lowered the expression of p27 and CDK6 only. BetA treatment of MDA-‐MB-‐231 cell line co-‐cultured with stromal cells lowered the expression of p21, p27 and Cyclin D1. 31
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BetA * BetA proved to be a potent anti-‐inflammatory, anti-‐ proliferative and anti-‐angiogenic agent against breast carcinoma MDA-‐MB-‐231 and MDA-‐MB-‐468 cell lines. * Given the fact that BetA treatment in vitro has been effective against TNBC, further studies are clearly warranted to determine its effect in vivo. * The effectiveness of BetA shows that it may be highly effective and has great potential in combination with conventional chemotherapeutic regimes therefore possibly enhancing the inhibition of tumour proliferation, inflammation and angiogenesis. [email protected]
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Panaxea Cory)Cur * Cory)Cur consists of Yanhusuo (Rhizoma Corydalis) and Ezhu (Rhizoma Curcumae) and has been an archaic Chinese medicine prescription since Song Dynasty (960-‐1279 AD). Cory)Cur was first recorded in ‘Ji Feng Pu Ji Fang (vol. 20)’ and ‘Zhu Shi Ji Yan Fang (vol. 10)’ in the Song dynasty, and used to improve blood circulation, to remove blood stasis, and to promote circulation for pain relief. * Both yanhusuo and ezhu could inhibit cancer cell proliferation, and ezhu induces cancer cell apoptosis, whereas yanhusuo was shown to inhibit metastasis.
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Panaxea Cory)Cur * Extracted by 95% ethanol, the ratio of 3:2 (ezhu to yanhusuo) results in Cory)Cur having strong synergistic antitumour effects in MDA-‐MB-‐231 cancer cells. * Findings by Gao et al., (2009) propose that the synergy observed in the cytotoxic effects of ezhu and yanhusuo in the human breast cancer cell line, MDA-‐MB-‐231, was caused by suppressing cancer cell proliferation and invasion. The mechanisms should be related with the down-‐regulation of phospho-‐ ERK1/2 and enhancement of the cytochrome c release.
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Corydalis * In another study, Gao et al. (2008) found that the yanhusuo extract inhibited the migration and invasion of MDA-‐MB-‐231 cells in vitro. In addition, the yanhusuo extract inhibited the mRNA expression and activity of MMP-‐9. * The anti-‐cancer metastasis effect of yanhusuo involved the activation of p38 and inhibition of ERK1/2 and SAPK/JNK mitogen-‐activated protein kinase (MAPK) signalling. * Nine alkaloids from the dichloromethane extract of C. yanhusuo and were tested for their aromatase binding activities. The results showed that the quaternary protoberberine alkaloids and the tertiary protoberberine alkaloids had aromatase binding activities (Shi et al., 2010) [email protected]
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Ganoderma lucidum * Ganoderma lucidum (ling zhi) suppresses phosphorylation of Akt on Ser473 and downregulates the expression of Akt, which results in the inhibition of NF-‐kappaB activity in MDA-‐ MB-‐231 cells. * The biological effect of Ganoderma lucidum was demonstrated by cell cycle arrest at G0/G1, which was the result of the downregulation of expression of NF-‐kappaB-‐ regulated cyclin D1, followed by the inhibition of cdk4. * Ganoderma lucidum suppresses the invasive behaviour of breast cancer by inhibiting the growth of MDA-‐MB-‐231 breast cancer (Jiang et al., 2004). [email protected]
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Strobilanthes crispus * Selected sub-‐fractions of the dichloromethane extract of S. crispus induced death of MCF-‐7 (breast), MDA-‐MB-‐231 (TNBC), PC-‐3 (prostate) and DU-‐145 (prostate) cells (Yaacob et al., 2010). * The combined Strobilanthes crispus leaves (SCS) and tamoxifen treatment displayed strong synergistic inhibition of MCF-‐7 and MDA-‐MB-‐231 cell growth at low doses of the anti-‐oestrogen. SCS further promoted the tamoxifen-‐induced apoptosis that was associated with modulation of mitochondrial membrane potential and activation of caspase-‐8 and caspase-‐9, suggesting the involvement of intrinsic and extrinsic signalling pathways (Yaacob et al., 2014). [email protected]
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Shiraia bambusicola * 11,11'-‐dideoxy-‐verticillin, a compound of the novel epidithiodioxopiprazine structural class, is isolated from the traditional Chinese medicinal herb Shiraia bambusicola (zhu huang) and has potent tyrosine kinase-‐inhibitory and anti-‐ tumour activities. * 11,11'-‐dideoxy-‐verticillin significantly inhibited the activities of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-‐1/fms-‐like tyrosine kinase-‐1 (VEGFR-‐1/ Flt-‐1) and human epidermal growth factor receptor-‐2 (HER2/ ErbB-‐2), with relative specificity on EGFR and VEGFR-‐1. MB-‐ MB-‐468 cells exhibited significant apoptotic morphological changes (Zhang et al., 2005). [email protected]
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TNBC * 50 cases of postoperative TNBC were given JLBSHJ formula orally, the control group consisting 50 cases took chemotherapy. 5-‐year observation was followed. * The survival rate was in the control group 80%, the treated group 94%; the life quality improving rate: the control group 68%, the treated group 90%; local recurrence rate: the control group 36%, the treated group 20%, remote metastasis rate: the control group 24%, the treated group 6%. * Total recurrence rate: the control group 76%, treated group 26%; bone marrow inhibition rate: the control group 90%, the treated group 10% [email protected]
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TNBC * Cellular immune function: CD4/CD8 ratio in the control group was (1.10±0.18), and the treated group was (1.47±0.30) (P<0.05); NK cell activity in the control group was (19.13±4.86), and(30.16±6.06) in the treated group (P<0.05). * Compared with chemotherapy regimen, the treatment of JLBSHJ on postoperative TNBC could prolong the survival rate of the patients, improve their life quality, increase cellular immune function, lower side and toxic effect, and lower remote metastasis rate (Hu Bei Zhong Yi Za Zhi. 2010, 32(6): 16-‐17)
[email protected]
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Ji Li Bu Shen He Ji Formula * Semen Astragali complanati (sha yuan zi or tong ji li) 30g * Radix Rehmanniae Glutinosae Praeparata (shu di) 20g * Radix Dioscoreae Oppositae (shan yao) 15g * Fructus Corni Officinalis (shan zhu yu) 10g
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* Fructus Lycii (gou qi) 15g * Radix Glycyrrhizae Uralensis Praeparata (zhi gan cao) 6g * Cortex Eucommiae Ulmoidis (du zhong) 15g * Cortex Cinnamomi Cassiae (rou gui) 3g * Radix Aconiti Carmichaeli Praeparata (fu zi) 15g
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TNBC * 40 cases of TNBC were averagely divided into 2 groups according to the patients’ choice, the treated group was given oral istration of herbs and had regular examination, the control group only had regular examination. * After a few years of clinical research, it’s found that TCM had positive therapeutic effect on TNBC, there’s significant difference compared with the control group. * TCM treatment on TNBC effectively controlled the recurrence and metastasis of these patients, prolonged the survival time and improved the life quality (Zhong Guo wu Zhen Xue Za Zhi. 2010, 10(19): 4566-‐4567). [email protected]
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Formula 2 * Rhizoma Iphigeniae Indicae (shan ci gu) 30g * Herba Solanum Nigrum (long kui) 30g * Radix Bupleuri (chai hu) 15g * Tuber Curcumae (yu jin) 15g * Rhizoma Sparganii Stoloniferi (san leng) 15g * Rhizoma Curcumae Ezhu (e zhu) 15g [email protected]
* Rhizoma Pinelliae Ternatae (ban xia) 12g * Spica Prunellae Vulgaris (xia ku cao) 15g * Concha Ostreae (mu li) 30g * Radix Glycyrrhizae Uralensis (gan cao) 10g * Radix Angelicae Sinensis (dang gui) 15g
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Oestrogen Receptor / Progesterone Receptor Positive
[email protected]
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Oestrogen Metabolism * The liver is a site for biosynthesis of oestrogens but it is also the main site for further biotransformation of them. Once the oestrogens are synthesised by aromatase in peripheral tissues including the liver, they will be released to the circulation. * Oestrone is in equilibrium with oestradiol and 17-‐b-‐ hydroxysteroid dehydrogenase (17bHSD) in this respect. The oestrogens are taken up by the liver where they will be bio-‐ transformed further in to different metabolites. The major oxidative routes of oestrone and oestradiol are 2-‐ and 4-‐ hydroxylation by cytochrome P450 (CYP) 2B1, 1A and 3A. Other minor oxidative pathways are also identified. [email protected]
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Oestrogen Metabolism * Oxidative metabolism of the oestrogens oestrone (E1) and oestradiol (E2) is the critical event in the initiation of cancer by oestrogens. E1 and E2 are oxidised by cytochrome P450 (CYP) to the catechol oestrogens 2-‐OHE1(E2) and 4-‐OHE1(E2) and then to the catechol oestrogen quinones, which react with DNA to form oestrogen-‐DNA adducts. * Oestrogen metabolism becomes unbalanced when expression of the activating enzymes CYP19 (aromatase) and CYP1B1 is higher and expression of the protective enzymes catechol-‐O-‐methyltransferase and quinone reductase is lower (Rogan & Cavalieri, 2011). [email protected]
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Oestrogen Metabolism * The 2-‐ and 4-‐hydroxy derivatives (and other metabolites) will be further converted to 2-‐ and 4-‐methoxy metabolites by catechol-‐O-‐methyltransferase (COMT). While the hydroxylated metabolites appear to result in DNA damage and contribute to the tumorigenic effect of oestrogen, the methoxy-‐derivatives appear to exhibit beneficial cardiovascular effects. * Oestrone and oestradiol and their metabolites undergo sulfation by sulfotransferases (SULTs) and glucuronidation by glucoronyltransferases (UGTs). Oestrone and oestradiol sulfates could be deconjugated by sulfatases (STs). [email protected]
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Oestrogen Metabolites * 16 alpha-‐OHE1 is a powerful metabolite that stimulates target tissues. Levels can rise in response to obesity, alcohol consumption, and toxic exposure. High levels of this potent metabolite are linked to increased risk and poorer prognosis in conditions linked to oestrogen excess such as breast cancer and lupus. * 4-‐hydroxyestrone (4-‐OHE1) – may react negatively with damaged DNA. It plays an important role in breast carcinogenesis because of its ability to induce DNA depurination independent of ER binding. 4OHE1 concentration, may have confounded results for oestrogen metabolite ratio (EMR). 48
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Metabolic Pathways * The two main pathways for metabolising oestrogen are via 16alpha-‐hydroxylation and 2-‐hydroxylation. The 16α-‐OHE1 metabolites are biologically active; the 2-‐OHE1 metabolites are not. It is suggested that women who metabolise a larger proportion of their endogenous oestrogen via the 16alpha-‐ hydroxy pathway may be at significantly elevated risk of breast cancer compared with women who metabolise proportionally more oestrogen via the 2-‐hydroxy pathway. * Studies by Ursin et al., (1997) and Cauley et al., (2003) do not the hypothesis that the ratio of the two hydroxylation metabolites (2-‐OHE1/16alpha-‐OHE1) is an important risk factor for breast cancer [email protected]
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Metabolic Pathways * There are indications that additional factors such as certain genetic polymorphisms and excessive oxidative stress are necessary to influence the synthesis of intermediate aggressive metabolites, which may already have gene toxicity at low concentrations and can destruct DNA structures and/ or have the potency to influence carcinogenesis by intensive proliferative actions (Mueck & Seeger, 2007). * It remains doubtful whether physiological oestradiol per se can be causally carcinogenic by proliferative processes (International Menopause Society, 2009).
[email protected]
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Oestrogen Metabolism Progesterone DHEA-‐S
Androstenedione
SHBG
Testosterone Oestrone Sulphate
Oestrodiol (E2) Oestrone (E1)
2-‐OHE1
4-‐OHE1
16α-‐OHE1
2-‐MeOE2
4-‐MeOE2
Oestriol (E3)
Carcinogenic metabolites are shown in red and anti-‐carcinogenic or neutral metabolites are shown in green.
Genes Evaluated by EstroGene Test * Phase I Detoxification * CYP1A1 * CYP1B1 * CYP3A4
Oestrone to 2-‐OH Oestrone (E1) Oestrone to 4-‐OH E1 Oestrone to 16-‐alpha OH E1
* Phase II Detoxification * COMT Methylation of 2-‐OH and 4-‐OH E1 * GST Quinones to Glutathione Conjugates * MnSOD Free Radicals Quenced https://www.estrogengenetest.com/ Enter: MPI license number for Practitioner discount
Botanicals & Oestrogen Metabolism * Panax notoginseng significantly increased mRNA expressions of GSTm1 and CYP1A1 in the 2 g·∙kg-‐1 and 4 g·∙kg-‐1 bw/d treatment groups, respectively, but P. notoginseng had a inhibitory tendency on mRNA expressions of CYP1B1 and significantly inhibited the expressions of CYP2B1 (Yang et al., 2009). * Rhizoma curcumae extract could increase and induce the enzyme activity and mRNA expression of CYP3A4 (Shao et al., 2008). * Flos Chrysanthemi, Fructus Lycii, Radix et Rhizoma Salviae Miltiorrhizae, Fructus Crataegi, Flos Lonicerae Japonicae, Rhizoma Dioscoreae are inducers of CYP3A4 (Xu et al., 2011). [email protected]
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Who Should be Tested to Reduce Breast Cancer Risk? * Women’s Health Initiative study first published in 2002 conclusively demonstrated the 2.5 increased breast cancer risk from cumulative oestrogen exposure. How can we pinpoint which women are more at risk? * By a genetic assessment of how a woman metabolizes oestrogen. Women with 3 or more genetic mutations have 2.5 to 13x greater breast cancer risk. All women should be tested to know if they possess the risk * Practically speaking, testing should take place when contemplating exogenous oestrogen use or for those with ER+ breast cancer history
Oral Contraceptives
In Vitro Fertilization
Hormone Replacement Therapy
Bio-‐identical Hormones
ER-‐Positive Breast Cancer
ER-‐Positive Breast Cancer Family History
Testing * It is appropriate to test every woman once in their lifetime, perhaps as part of an initial gynecological screening. Practically speaking, the Oestrogen Gene Tests should be ordered when before prescribing exogenous oestrogens. For example, prior to starting oral contraception, hormone replacement therapy or bio-‐identical hormones, and especially IVF. All women with current or previous exposure should be tested. * Certainly, women with a history of oestrogen receptor-‐ positive breast cancer need to know or that they have multiple snps and add oestrogen metabolism improvement techniques to their standard breast cancer treatment. [email protected]
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Erα vs ERβ * The oestrogen receptor (ER) isoform known as ERβ has become the focus of intense investigation as a potential drug target. The existence of clear-‐cut differences in ERβ and ERα expression suggests that tissues could be differentially targeted with ligands selective for either isoform (Couse et al., 1997; Enmark et al., 1997). * In particular, the fact that ER β is widely expressed but not the primary oestrogen receptor in, for example, the uterus (Harris, Katzenellenbogen, & Katzenellenbogen, 2002) opens up the possibility of targeting other tissues while avoiding certain classical oestrogenic effects. [email protected]
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Daidzein * Charalambous, Pitta & Constantinou (2013) found that equol (>50 μM) and 4-‐hydroxy-‐tamoxifen (4-‐OHT; >100 nM) both significantly reduced the breast cancer MCF-‐7 cell viability. Daidzein and its metabolite S-‐(-‐)-‐equol showed the potential of inhibiting the growth of mammary tumours. Daidzein or S-‐ (-‐)-‐equol could be used as a core structure to design new drugs for breast cancer therapy. Our results indicate that consumption of daidzein may protect against breast cancer (Liu et al., 2012). * Daidzein could induce breast cancer cell apoptosis through the mitochondrial caspase-‐dependent cell death pathway (Jin et al., 2010). [email protected]
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S-‐Equol * The soy isoflavone daidzin was isolated and shown to be a precursor to equol (Axelson et al., 1982). It was also found that the introduction of soy protein to the diet led to an increased excretion of equol in some but not all adults (Setchell et al., 1984). * The finding of high concentrations of equol, a nonsteroidal oestrogen; in the urine of adults consuming fermented soy foods prompted the hypothesis that this nonsteroidal oestrogen may be beneficial in the prevention and treatment of many hormone-‐dependent conditions.
[email protected]
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Erα vs ERβ * Isoflavone (genistein) consumption indicate the possible contribution of ERβ-‐specific signalling in breast cancer prevention. A selective oestrogen receptor modulator, which works as an antagonist of ERα and an agonist of ERβ, may be a promising chemo-‐preventive treatment (Saji, Hirose, & Toi, 2005). * ERβ works as counter partner of ERα through inhibition of the transactivating function of ERα by heterodimerization, distinct regulation on several specific promoters by ERα or ERβ, and ERβ-‐specific regulated genes which are probably related to its anti-‐proliferative properties [email protected]
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Genistein * Genistein significantly decreased both gene and protein expression of Rho GTPases (Rho, Rac, and Cdc42) and the downstream effector of Rac and Cdc42, PAK1, are significant for understanding the mechanism by which genistein inhibits cancer cell invasion, and may reduce breast cancer progression via transcriptional regulation (Vadlamudi et al., 2004; Vega & Ridley, 2008). * Genistein is a potent inhibitor of the growth of the human breast carcinoma cell lines, MDA-‐468 (oestrogen receptor negative), and MCF-‐7 and MCF-‐7-‐D-‐40 (oestrogen receptor positive). The presence of the oestrogen receptor is not required for the isoflavones to inhibit tumour cell growth 60 16/12/14 (Peterson & Barnes, 1991)
Genistein * Results also suggest that genistein could be useful as a chemotherapeutic agent in premenopausal women with breast cancer of the ERα-‐negative and ERβ-‐positive type (Rajah et al., 2009). * ERβ has been postulated to play a role in modulating ERα-‐ mediated cell proliferation, genistein and quercetin may be agonists for both receptor types and the ratio of ERα to ERβ is known to vary between tissues and results point at the importance of the cellular ERα/ERβ ratio for the ultimate effect of phytoestrogens on cell proliferation (Sotoca et al., 2008). [email protected]
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See * Daniel Weber. Phytoestrogens and Cancer. Cancer Strategies Journal Winter 2014
[email protected]
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Erα vs ERβ * Selective ER agonists can stimulate either ER-‐α or ER-‐β and induce tissue-‐specific oestrogen-‐like effects. MF-‐101 is derived from 22 herbs that are traditionally used in Chinese medicine for the treatment of menopausal symptoms. * Studies with the MF-‐101-‐isolated active compounds, liquiritigen and chalcone, demonstrated selectivity for ER-‐β, with no induction of proliferative events. MF-‐101 did not promote the growth of breast cancer cells or stimulate uterine tissue (Stovall & Pinkerton, 2009). * MF101, a selective oestrogen receptor β agonist is a safe and effective for treating menopausal hormone therapy and nighttime awakenings (Leitman & Christians, 2012). [email protected]
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MF101 * Scutellaria barbata (Ban Zhi Lian) * Atractylodes macrocephala (Bai Zhu) * Rheum palmatum (Da Huang) * Wolfiporia extensa (Fu Ling) * Triticum aestivum (Fu Xiao Mai) * Glycyrrhiza uralensis (Gan Cao)
* Pueraria montana (Ge Gen) * Glycine max (Hei Dou) * Achyranthes bidentata (Huai Niu Xi) * Huang Qi (Astragalus mongholicus) * Lian Zi Xin (Nelumbo nucifera) * Paeonia suffruticosa (Mu Dan Pi)
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MF101 * Mu Li (Crassostrea gigas) * Nu Zhen Zi (Ligustrum lucidum) * Sheng Di Huang (Rehmannia glutinosa) * Shan Dou Gen (Sophora tonkinensis) * Shan Zhu Yu (Cornus officinalis) * Suan Zao Ren (Ziziphus jujuba)
* Tian Men Dong (Asparagus cochinchinensis) * Epimedium spp. (Yin Yang Huo) * Anemarrhena asphodeloides (Zhi Mu) * Ze Xie (Alisma plantago-‐ aquatica) * Chalcone * Liquiritigenin
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Chalcone * Hsu et al., (2006) examined (1,3-‐diphenyl-‐2-‐propenone) for its effect on proliferation in human breast cancer cell lines, MCF-‐7 and MDA-‐MB-‐231. The results showed that chalcone inhibited the proliferation of MCF-‐7 and MDA-‐MB-‐231 by inducing apoptosis and blocking cell cycle progression in the G2/M phase. * Chalcone extracted from Taraxacum officinale also triggered the mitochondrial apoptotic signalling by increasing the amount of Bax and Bak and reducing the level of Bcl-‐2 and Bcl-‐XL, and subsequently activated caspase-‐9 in MCF-‐7 and MDA-‐MB-‐231 cells. [email protected]
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Liquiritigenin (LQ) * LQ separated from Glycyrrhiza radix, possesses anti-‐ inflammatory, anti-‐hyperlipidaemic, and anti-‐allergic effects. The expression of cleaved PARP, the hall-‐marker of apoptosis, was enhanced by LQ. LQ treatment also resulted in a reduction of the expressions of B-‐cell lymphoma 2 (Bcl-‐2) and B-‐cell lymphoma-‐extra large (Bcl-‐xL), and an increase of the phosphorylation of c-‐Jun N-‐terminal kinases (JNK) and P38. * LQ suppressed the activation of extracellular signalling-‐ regulated kinase (ERKs) and reduced the translocation of phosphor-‐ERKs from cytoplasm to nucleus (Wang et al, 2014). [email protected]
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ER+/PR+ * Ganoderma lucidum and Scutellaria baicalensis, have been reported to suppress ER expression in vitro (Jiang, Slivova & Sliva, 2006; Chung et al., 2008). * Cryptotanshinone has been recently evaluated for its anti-‐ cancer activity and is a potent stimulator of ER stress, leading to apoptosis in many cancer cell lines including MCF7 breast carcinoma. * Cryptotanshinone also evidenced sensitising effects to a broad range of anti-‐cancer agents including Fas/Apo-‐1, TNF-‐α, cisplatin, etoposide or 5-‐FU through inducing ER stress, highlighting the therapeutic potential in the treatment of breast cancer (Park et al., 2012). [email protected]
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ER+/PR+ * Tanshinone IIA is a widely used Chinese herbal medicine isolated from Danshen (Salvia miltiorrhiza) that may have anti-‐ inflammatory and anti-‐oxidant properties, as well as cytotoxic activities against multiple human cancer cell lines. * Tanshinone IIA might have potential anti-‐cancer activity that is stronger than tamoxifen in both ER-‐positive and ER-‐negative breast cancers. This function could be attributed in part to its inhibition of proliferation and apoptosis induction in cancer cells via the downregulation of multiple genes involved in cell cycle regulation, cell proliferation, apoptosis and DNA synthesis (Lu et al., 2009). [email protected]
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Panaxea Tanshins * Salvia Miltiorrhiza (contains standardised extracts Tanshinone IIA and Cryptotanshinone) * Cytotoxic * Apoptoxic * Inhibits angiogenesis
[email protected]
* Clears Heat and eliminates toxins, activates blood circulation, dispels stasis, generates body fluids, dispels wind and opens channels and collaterals.
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ER+/PR+ * DNA microarray technology has been used to understand the molecular mechanism underlying the anti-‐cancer effect of berberine carcinogenesis in two human breast cancer cell lines, the ER-‐positive MCF-‐7 and ER-‐negative MDA-‐MB-‐231 cells; specifically, whether it affects the expression of cancer-‐related genes. * Treatment of the cancer cells with berberine markedly inhibited their proliferation in a dose-‐ and time-‐dependent manner. The growth-‐inhibitory effect was much more profound in MCF-‐7 cell line than that in MDA-‐MB-‐231 cells (Kang et al., 2005). [email protected]
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Metalloestrogens * Aluminium chloride or aluminium chlorhydrate can interfere with the function of oestrogen receptors of MCF7 human breast cancer cells both in of ligand binding and in of oestrogen-‐regulated reporter gene expression. * This adds aluminium to the increasing list of metals capable of interfering with oestrogen action and termed metalloestrogens (Darbre, 2005). * Other metalloestrogens are arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin (Byrne et al., 2013). [email protected]
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Emodin & Aloe-‐emodin * Huang et al., (2013) reported results that indicated both emodin and aloe-‐emodin are capable of inhibiting breast cancer cell proliferation by down-‐regulating ER α protein levels, thereby suppressing ER α transcriptional activation. Furthermore, aloe-‐emodin treatment led to the dissociation of heat shock protein 90 (HSP90) and ER α and increased ER α ubiquitination. * Data demonstrate that emodin and aloe-‐emodin specifically suppress breast cancer cell proliferation by targeting ER α protein stability through distinct mechanisms.
[email protected]
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Emodin & Aloe-‐emodin * Huang, Chen, Shi (2008) focused on the effect of emodin in human breast cancer BCap-‐37 cells and further understand the underlying molecular mechanism in treating breast cancer. * The results of the study further showed that Bcl-‐2 level decreased, while Bax and cytosolic cytochrome c levels in sample cells increased after the emodin treatment. The decline in the Bcl-‐2/Bax ratio and the increase of cytosolic cytochrome c concentration were consistent with the increase of the apoptotic ratio.
[email protected]
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Panaxea Emodin * Recent research has suggested * Panaxea Emodin Complex that plant polyphenols such as extracted from Rheum Palmatum (da huang) contains emodin may be used to sensitise tumour cells to Emodin (1, 3, 8 -‐ trihydroxy -‐ 6 chemotherapeutic agents and – methylanthraquinone) and radiation therapy by inhibiting Glycyrrhiza Uralensis extract pathways that lead to (gan cao) treatment resistance. Such agents have also been found to be protective from therapy-‐ associated toxicities (Garg et al., 2005) [email protected]
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Panaxea D:Fend * 350mg Daidzein/Daidzin * 470 mg Genistein/Genistin * 110 mg Glycitein/Glycitin Taken with * MicrSoy-‐20 (MS-‐20) or * Haelan 951 (Bachg & Haselhorst, 2007) Or * FSP [email protected]
* MS-‐20 demonstrated its ability to restore chemotherapy-‐ induced immunosuppression and improve quality of life (Chi et al., 2014). * Fermented soy product (FSP) was most efficient in tumour containment, possibly due to a positive modulation of the immune system (Kinouchi et al., 2012) 76
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FSP * FSP caused apoptotic cell death in MCF-‐7 cells. FSP induced generation of reactive oxygen species (ROS) indicating that the ROS production probably was the cause of this apoptotic cell death. This study suggests that FSP retards tumour growth in vivo and can trigger apoptosis in vitro (Chang et al., 2002). * Daily ingestion of the probiotic soy product may contribute to a beneficial balance of the faecal microbiota and this modulation is associated with an improved cholesterol profile (Cavallini et al., 2011).
[email protected]
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Haelan * Haelan helps repair DNA damage, thereby allowing chemotherapy to be more effective. * Haelan is anti-‐angiogenic, and pro-‐apoptotic. * Haelan may disrupt signals of epidermal Growth Factor Receptors; possibly blocking the signals altogether. * Haelan may cause a reactivation of the P53 tumour suppressor protein for these specific patients * Haelan is known to shut off the Nuclear Factor Kappa Beta (NF-‐Kb) mutation capability completely.
[email protected]
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D:FEND * D:FEND normalises cell function and contains herbal phytoestrogens. Phytoestrogens are plant-‐derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits is frequently attributed to phytoestrogens. D:Fend induces apoptosis via the mitochondrial pathway (Stark & Madar, 2002). * It is involved in cell cycle arrest, antiangiogenic potential, antimetastatic potential and in enhancing radiotherapy treatment. In various cancer models phytoestrogens significantly inhibit tumour growth, invasion and metastasis (Virk-‐Baker et al., 2010; Vitale et al., 2013) [email protected]
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Oldenlandia diffusa (OD) * Gu et al., (2012) observed that extracts bai hua she she cao strongly inhibited anchorage-‐dependent and -‐independent cell growth and induced apoptosis in oestrogen receptor alpha (ERα)-‐positive breast cancer cells, whereas proliferation and apoptotic responses of MCF-‐10A normal breast epithelial cells were unaffected. * Mechanistically, OD extracts enhance the tumour suppressor p53 expression as a result of an increased binding of ERα/Sp1 complex to the p53 promoter region. * OD exerts antiproliferative and apoptotic effects selectively in ERα-‐positive breast cancer cells. [email protected]
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Resveratrol & Ursolic Acid * Resveratrol, a phytoalexin, and ursolic acid, a pentacyclic triterpenoid, are two bioactive compounds that have anti-‐ inflammatory actions, induce apoptosis and have anti-‐cancer activities by targeting signal pathways. * Ursolic acid treatments of MCF-‐7 breast cancer cells induced apoptosis through internal mitochondrial pathways (Kassi et al., 2009). This finding is further substantiated when on treating MDA-‐MB-‐231 cells with ursolic acid an induction of mitochondrial mediated cancer cell apoptosis was observed (Kim et al., 2011). Ursolic acid was found to release cytochrome C from the mitochondria to the cytosol, to up-‐ regulate the Bax protein as well as a down-‐regulate Bcl-‐2. [email protected]
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Ursolic Acid * UA was found to inhibit the proliferation of MCF-‐7 cells in a concentration and time-‐dependent manner. After treatment, UA-‐induced apoptosis was accompanied by a significant decrease in CyclinD1/CDK4 expression, which can be regulated by FoxM1. Previous studies demonstrated that FoxM1 orchestrates the transcription of genes that are essential for cell cycle progression and cell proliferation (Wang, Ren, Xi, 2012). * UA-‐induced apoptosis (53 μM), the PARP cleavage, and decreased Bcl-‐2 protein (53 μM) to the notion that UA induces apoptosis through the intrinsic mitochondrial pathway (Kassi et al., 2009). [email protected]
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Panaxea Ursolic Acid * We use only pharmaceutical grade UA that is micronised for greater bio-‐availability. Most UA that is commercially available is either industrial or cosmetic grade.
[email protected]
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Panaxea antiEST * The actions of unopposed oestrogen or oestrogen in the face of progesterone (P) resistance can promote various gynaecologic disorders, including endometriosis, endometrial hyperplasia, and cancer. * Collins et al., (2009) investigated the botanical herb Prunella vulgaris (PV) and found that extracts of this plant have anti-‐ oestrogenic activities. * Methanol extract of PV exhibits significant anti-‐oestrogenic properties, both in vitro and in vivo. This activity is likely due to the ability of PV-‐activated aryl hydrocarbon receptor (AHR) to interfere with oestrogen [email protected]
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HER2/neu
[email protected]
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HER-‐2/neu * HER2 is a member of the epidermal growth factor receptor (EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. * In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. * It is strongly associated with increased disease recurrence and a poor prognosis. Over-‐expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma. [email protected]
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HER-‐2/neu * The amplification and overexpression of the HER-‐2/neu proto-‐ oncogene, which encodes the tyrosine kinase receptor p185neu, have been observed frequently in tumours from human breast cancer patients and are correlated with poor prognosis. * Results indicate that emodin inhibits HER-‐2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-‐2/neu-‐overexpressing cancer cells (Zhang et al., 1995; Zhang et al., 1999).
[email protected]
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P53 & Ki67 * The Ki67 marker and P53 protein are important factors in the HER-‐2/neu breast cancer patients with emphasis on therapeutic agents. Results of the study suggested that the p53 protein and Ki67 marker are important factors in the prognosis of metastasis and survival rate in patients with breast cancer. * It is important that patients of Immunohistochemistry (IHC 2+) with Ki67 positive or p53 positive get treated with adjuvant therapy (Payandeh et al., 2014).
[email protected]
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P53 & Ki67 * Scutellaria baicalensis increased expression of p53 in the cancer cells of key proteins related to the enhancement of apoptosis is observed (Gao et al., 2011). Similarly, Gleditsia sinensis thorns are used as a medicinal herb, which shows a decrease in cell growth and an increase in cell cycle arrest during the G2/M-‐ phase. The arrest is correlated with increased p53 levels and down-‐regulation of cyclinB1 (Lee et al., 2010). * Ki-‐67, a nuclear antigen, is widely considered as a marker of cellular proliferation. With Radix Sophorae Tonkinesis and Rhizoma Curcumae expression of Ki-‐67 antigen was significantly different in the normal, hyperplastic and mild dysplastic cancers (Zhou & Zhang, 2005). 89
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HER-‐2/neu * After surgery selected HER2/neu transgenic spontaneous breast tumour model mice were randomly divided them into control group, traditional Chinese medicine group (RSR group), western medicine group (Trastuzumab group), and the combination group (RSR and Trastuzumab group) and treated with corresponding medicine for 4 month. * “Ru’ai Shuhou Recipe” can inhibit recurrent tumour volume in transgenic mice after operation, block the HER2-‐mediated p38 MAPK and PI3K-‐Akt signal pathways, inhibit tumour cell proliferation and promote tumour cell apoptosis (Shao et al., 2013). [email protected]
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Ru Ai Shu Hou Fang * Rhizoma Alocasiae Macrorrhizae (she liu gu) (decocted first) 60g * Radix Astragali (huang qi) 30gm * Radix Codonopsis (dang shen) 12gm * Radix Atractylodes (bai zhu) 10gm * Herba Epimedii (yin yang huo) 15gm [email protected]
* Radix Adenophorae (nan sha shen) 15g * Rhizoma Curcumae Ezhu (e zhu) 30gm * Herba Salviae Chinensis (shi jian chuan) 30gm * Radix Ledebouriellae Divaricatae (feng fang) 12gm * Cornu Cervi gel (lu jiao pian) 12gm 91
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Ru Ai Shu Hou Fang * Herba Sargassii (hai zao) 30gm * Herba Cistanches (rou cong rong) 12gm * Radix Achyranthis Bidentatae (huai niu xi) 30gm * Fructus Psoraleae Corylifoliae (bu gu zhi) 30gm * Concha Ostreae calcined (duan mu li) 30gm * Rhizoma Curcumae Longae (jiang huang) 30gm 92 * Poria Cocos (fu ling) 12gm
* Os Draconis calcined (duan long gu) 30gm * Radix Cynanchi Paniculati (xu chang qing) 30gm * Gummi Olibanum (ru xiang) 10gm * Herba Scutellariae Barbatae (ban zhi lian) 30gm * Rhizoma Corydalis (yan hu suo) 30gm * Scolopendra Subspinipes (wu gong) 3gm 16/12/14
HER-‐2/neu * Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. * Inhibition of HER-‐2 signalling by specific human epidermal growth receptor 1/HER-‐2 (EGFR/HER-‐2) kinase inhibitor lapatinib synergistically enhanced the anti-‐cancer effects of honokiol in HER-‐2 over-‐expressed breast cancer cells (Liu et al., 2008) [email protected]
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HER-‐2/neu * The anthocyanins cyanidin-3-glucoside (C3G) and peonidin-3-glucoside from Hibiscus sabdariffa have been identified as potential drugs for the therapy of HER2-positive breast cancer. They have been used as supplements in targeted therapeutics and chemotherapeutics in Asia. * The combination treatments induced apoptosis, inhibited cell growth and affected HER2 and its downstream signalling pathway in MDA-MB-453, BT474 and HCC1569 cells, the effects were synergistic. The combination of 3CG and trastuzumab (Trast) inhibited tumour growth in an in vivo xenograft model. The data from the present study suggested that C3G exhibits potent antitumour activity when combined with Trast (Liu et al., 94 16/12/14 2014)
HER-‐2/neu * Tyrosine kinase inhibitors such as emodin can target the HER2/ neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-‐overexpressing breast cancer cells. * Emodin also sensitises HER2/neu-‐overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene (Wang et al., 2001).
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HER-‐2/neu * The combination of emodin AMAD treatment and siRNA against Her2 synergistically inhibited proliferation and induced apoptosis. Taken together, these data suggest that blockade of Her2/neu binding to Hsp90 and following proteasomal degradation of Her2/neu were involved in emodin azide methyl anthraquinone derivative (AMAD)-‐induced apoptosis in Her2/ neu-‐overexpressing cancer cells (Yan et al., 2011).
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HER-‐2/neu * As an anti-‐cancer agent, emodin has been shown to suppress the growth of various tumour cell lines including hepatocellular carcinoma, pancreatic, breast, colorectal, leukaemia, and lung cancers. * Emodin is a pleiotropic molecule capable of interacting with several major molecular targets including NF-‐κB, casein kinase II, HER2/neu, HIF-‐1α, AKT/mTOR, STAT3, CXCR4, topoisomerase II, p53, p21, and androgen receptors which are involved in inflammation and cancer.
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HER-‐2/neu * Apigenin exhibited potent growth-‐inhibitory activity in HER2/ neu-‐overexpressing breast cancer cells. Apigenin-‐induced cellular effects result from loss of HER2/neu and HER3 expression with subsequent inactivation of PI3K and autologous tumour killing (ATK) pathways in cells that are dependent on this pathway for cell proliferation. * This implies that the inhibition of the HER2/HER3 heterodimer function provided an especially effective strategy for blocking the HER2/neu-‐mediated transformation of breast cancer cells. * The degradation of mature HER2/neu involves polyubiquitination of HER2/neu and subsequent hydrolysis by the proteasome (Way et al., 2005). [email protected]
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HER-‐2/neu * Melatonin exhibits anti-‐inflammatory and anticancer effects and could be a chemopreventive and chemotherapeutic agent in human Her-‐2 positive MDA-‐MB-‐361 breast cancer cells. Melatonin markedly inhibited phosphorylation of PI3K, Akt, PRAS40, and GSK-‐3 proteins, thereby inactivating the PI3K/Akt signalling pathway. * It induces Apaf-‐1 expression, triggered cytochrome C release, and stimulated caspase-‐3 and caspase-‐9 activities and cleavage, leading to an activation of the Apaf-‐1-‐dependent apoptotic pathway. * It inhibits cell proliferation and induces apoptosis by simultaneously suppressing the COX-‐2/PGE2, p300/NF-‐κB, and 99 16/12/14 PI3K/Akt/signalling (Wang et al., 2012).
Other Pathways
Breast Cancer
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Bax and Bcl-‐2 * The balance between Bax and Bcl-‐2 in favour of the former. The ratio of Bax to Bcl-‐2 is a useful index to evaluate tumour apoptosis induced by Kupffer cells. An experiment by Chen et al., (2002) suggests that alteration of the ratio of Bax to Bcl-‐2 may result from increased levels of iNOS and TNFα. * The combined assessment of Bcl-‐2 and Bax protein expression may be used to predict a clinical response to chemoradiation therapy based on the Bax/Bcl-‐2 ratio determined before therapy. The Ki-‐67 index may be a useful predictor of this prognosis (Matsumoto et al., 2004).
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SZKJT * There are only a few mechanistic studies on the action of TCM formulas as anticancer agents. One study was on San Zhong Kui Jian Tang (SZKJT), a complex formula comprising 17 different herbs, that is used for cancer therapy in China. * SZKJT was found to induce the mitochondrial apoptotic pathway by changing Bax/Bcl-‐2 ratios, cytochrome c release and caspase-‐9 activation in two human breast cancer cell lines, MCF-‐7 and MDA-‐MB-‐231 (Hsu et al., 2006). * Mitochondrial oncoproteins, such as bcl-‐2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel pro-‐apoptotic molecules in order to circumvent chemoresistance (Del Poeta et al., 2002). [email protected]
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SZKJT * Thallus Eckloniae (kun bu) * Cortex Phellodendri (huang bai) * Rhizoma Anemarrhenae (zhi mu) * Radix Platycodi (Jie Geng) * Rhizoma Sparganii (san leng) * Rhizoma Curcuma (e zhu) * Fructus Forsythiae (lian qiao) * Rhizoma Coptidis (Huang Lian) * Radix Glycyrrhizae Preparata (zhi gan cao)
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Radix Scutellariae (huang qin) Radix Paeoniae Alba (bai shao) Radix Puerariae (ge gen) Radix Bupleuri (chai hu) Extremitas Radix Angelicae Sinensis (dang gui wei) Radix Gentianae (long dan cao) Radix Cimicifugae (sheng ma) Radix Trichosanthis (tian hua fen) Rhizoma Zingiberis (sheng jiang) 16/12/14
Leonurus japonicus (yi mu cao) * Data suggest that leonurus aqueous & ethanol extract may effectively inhibit the proliferation of breast cancer cells through mechanisms of both cytotoxicity and cell cycle arrest. The cellular effects of the extract are non-‐apoptotic and ER independent on breast cancer cells. * The 70% ethanol extract in vivo markedly suppressed the development of uterine adenomyosis and mammary cancers, while the aqueous extract was previously reported to have anti-‐cancer activity in breast cancer cells with low potency (Tao et al., 2009).
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Shenqi Fuzheng Injection * In regard to advanced breast cancer, the herbal preparation Shenqi Fuzheng Injection (SFI), was demonstrated to alleviate bone marrow inhibition and cellular immunity suppression caused by chemotherapy, and to relieve clinical symptoms, raise the quality of life and prolong survival time compared to patients receiving only chemotherapy. * The total short-‐term remission rate, the improvement rate of clinical syndrome and quality of life was 50.0%, 70.0% and 76.7% in the treatment group, and 43.3%, 46.7% and 50.0% in the control group, respectively, showing significant difference between the two groups (all P < 0.05). [email protected]
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Shenqi Fuzheng Injection * The occurrence of adverse reaction in the treatment group was lower than that in the control group (P < 0.05). The level of CD3+ CD4+ and CD4+/CD8+ ratio increased (P < 0.05) and CD8+ decreased in the treatment group (P < 0.01), while they showed insignificant change in the control group (Huang et al., 2008). * SFI can improve and regulate immune function of the patients with local advanced breast cancer given the neoadjuvant chemotherapy, and therefore it can enhance the curative effect and reduce the side effect as well. An obvious rise of the T-‐lymphocyte subgroup and NK cells was found in the study group after the neoadjuvant chemotherapy, with a very 16/12/14 significant difference from the 106 controls (P < 0.01).
Shenqi Fuzheng Injection * Shenqi Fuzheng is a newly developed injection concocted from two kinds of Chinese medicinal herbs: Radix Astragali (huang qi) and Radix Codonopsis (dang shen) (Yang & Xu, 2004; Lu & Lu, 2006). * It was approved by the State Food and Drug istration of the People’s Republic of China in 1999 primarily as an antitumour injection to be manufactured and marketed in China (Zhong, 2009).
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MDR Breast Cancer * Paris saponin VII (PS VII), a kind of saponin, from Trillium tschonoskii (yan ling cao) dose dependently suppressed cell viability as well as triggered apoptosis and modulated drug resistance of MCF-‐7/ADR cells. * Further results showed that PS VII treatment in MCF-‐7/ADR cells led to increased TNFR1, TRAIL R1/DR4, TRAIL R2/DR5, and FADD expression, and activation of PARP, caspase-‐8, and 3. In parallel to the alterations, P-‐glycoprotein expression and activity were also reduced. * These findings showed that PS VII might be an effective tumouristatic agent for the treatment of MDR breast cancer (Li et al., 2014). [email protected]
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Breast METS * MDA-‐MB-‐231 cell line is a highly metastatic breast cancer cell line. The results demonstrated by Kim et al., (2008) that treatment with berberine inhibits growth in both MDA-‐MB-‐231 and MCF-‐7 cells. This partly occurs through the induction of apoptosis in MDA-‐MB-‐231 cells, and through both cell cycle arrest and induction of apoptosis in MCF-‐7 cells. * Ursolic acid, a naturally occurring triterpenoid, has various anticancer activities. In this study, Yeh, Wu & Yen (2010) observed that ursolic acid exerted a dose-‐ and time-‐dependent inhibitory effect on the migration and invasion of highly metastatic breast MDA-‐MB-‐231 cells at non-‐cytotoxic concentrations. [email protected]
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Breast METS * The effect of berberine on invasion, migration, metastasis, and angiogenesis is mediated through the inhibition of focal adhesion kinase (FAK), NF-‐κB, urokinase-‐type plasminogen-‐activator (u-‐PA), matrix metalloproteinase 2 (MMP-‐2), and matrix metalloproteinase 9 (MMP-‐9) (Ho et al., 2009; Hamsa & Kuttan. (2011) * Reduction of Rho kinase-‐mediated Ezrin phosphorylation (Tang et al., 2009); reduction of the expression of COX-‐2, prostaglandin E, and prostaglandin E receptors (Singh et al., 2011) * Down-‐regulation of hypoxia-‐inducible factor 1 (HIF-‐1), vascular endothelial growth factor (VEGF) and pro-‐inflammatory mediators (Jie et al., 2011; Hamsa & Kuttan, 2012). 110
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Breast METS * Berberine also inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell-‐cycle arrest. Anoikis, or detachment-‐induced apoptosis, may prevent cancer progression and metastasis by blocking signals necessary for survival of localised cancer cells. Resistance to anoikis is regarded as a prerequisite for metastasis. * The anoikis-‐resistant cells have a reduced growth rate and are more invasive than their respective adherent cell lines. The effect of berberine on growth was compared to that of doxorubicine in both the adherent and anoikis-‐resistant cell lines. Berberine promoted the growth inhibition of anoikis-‐resistant cells to a greater extent than doxorubicine treatment (Kim et al., 2010). 111
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Panaxea Berberine Complex * Berberine is an anticancer agent by three different cell lines which were MCF-‐7, HepG-‐2, and Caco-‐2 cells by using neutral red uptake assay which compared with control normal cells (PBMC). Berberine chloride and barberry extract showed to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (Abeer et al., 2013). Berberine has been established to inhibit the growth of breast cancer cells. * Treatment with berberine-‐induced cell cycle arrest at G0/G1 in the anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 cells as compared to untreated control cells. These results revealed that berberine can efficiently inhibit growth by inducing cell cycle arrest in anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 cells (Kim et al., 2010). 112
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Panaxea CoryBer * Gao et al., (2008) found that the yanhusuo extract inhibited the migration and invasion of MDA-‐MB-‐231 cells in vitro. The yanhusuo extract inhibited the mRNA expression and activity of metalloproteinase-‐9 (MMP-‐9). The anti-‐cancer metastasis effect of yanhusuo involved the activation of p38 and inhibition of ERK1/2 and SAPK/JNK mitogen-‐activated protein kinase (MAPK) signalling. * Oh et al., (2010) identified the biological activity of yanhusuo against cancer metastasis. Corydalis alkaloid (CA) inhibited LPS-‐ induced IL-‐8 production in a dose-‐dependent manner. CA inhibited extracellular signal-‐regulated kinase and p38 MAPK phosphorylation, which suggests that CA inhibits IL-‐8 secretion 113 16/12/14 by blocking MAPK phosphorylation.
Panaxea CoryBer * Corydalis alkaloids containing Tetrahydropalmatine (dl-‐ thp) Rhizoma Coptidis Recens containing berberine (75%)
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Pain * Research suggests that dl-‐ THP blocks certain receptor sites (e.g., dopamine) in the brain to cause sedation. Reports from Chinese researchers have noted that the herb was effective in reducing pain in seventy-‐eight per cent of the patients tested (Oh et al., 2010). 114
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Breast METS * Hu et al., (2014) istered Chinese traditional herb drugs called Fei Decoction to help a patient with breast cancer multiple pulmonary and skeletal metastatic lesions. After taking the Chinese herbs for 2 months, the tumour marker (CEA, CA15-‐3) dramatically decreased, resulting in the normal range. * Both lung and bone metastatic sites reduced according to CT and ECT imaging, and the patient felt free from the complaint of pulmonary and cardiac discomfort. * The PFS (progression-‐free-‐survival) and TTP (time-‐to-‐ progression) from the onset to date is notable. [email protected]
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Fei Decoction * Semen Coicis (yi yi ren) * Semen Persicae (tao ren) Semen Benincasae (dong gua zi) * Radix Astragali membranaceus (huang qi) * Bulbus Lilii (bai he) * Cortex albiziae (he huan pi) Radix Ophiopogonis (mai men dong) * Rhizoma bletillae (bai ji) * Bulbus fritillariae cirrhosae (chuan bei mu)
* Semen Persicae (tao ren) Radix Platycodonis grandiflorum (jie geng) * Herba Houttuynia cordata (yu xing cao) * Radix Glehniae (bei sha shen) Radix Cynanchi atrati (bai wei) Radix Glycyrrhizae (gan cao) * Fructus Oryzae Germinatus Praeparata (jiao dao ya) * Fructus Hordei Germinatus Praeparata (jiao mai ya) 116 16/12/14
Hyperprolactinaemia * Prolactin levels were measured in 149 patients with advanced metastatic breast cancer and Hyperprolactinaemia occurs in 44% of patients with metastatic breast cancer in the course of the disease. HYPRL is associated with progressive breast cancer in 88% of cases. * It is concluded that HYPRL is of prognostic significance and a reliable indicator of progressive disease in advanced metastatic breast cancer (Holtkamp et al., 1984). * Hyperprolactinaemia is associated with aggressiveness of the tumour, early disease relapse or metastases, and poor overall survival in patients with node negative breast cancer (Patel et al., 1996). 117
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Hyperprolactinaemia * The formula Huiru Yizeng Yihao significantly decreased prolactin (PRL) and increased oestradiol (E2), progesterone (P), follicle stimulating hormone (FSH), luteinizing hormone (LH) concentrations of hyperprolactinaemia rats. * It decreased E2, PRL, FSH, gonadotropin-‐releasing hormone (GnRH), 5-‐hydroxytryptamine (5-‐HT) and increased P concentrations of human menopausal gonadotropin (hMG). * Treatment could significantly regulate the sex hormone disorder of hyperprolactinemia (Wang et al., 2013).
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Huiru Yizeng Yihao * Mai Ya (Fructus Hordei Germinatus) * Xia Ku Cao (Prunella vulgaris L.) * Bai Shao (Paeonia lactiflora) Pallas) * Zhe Bei Mu (Fritillaria thunbergii Miq. * Ru Xiang (Boswellia carterii Birdw.) * Yu Jin (Curcuma aromatica Salisb.) * Dan Shen (Salvia miltiorrhiza Bge.) * Bai Jie Zi (Semen Brassicae) * Mu Li (Ostrea gigas thunberg) * Kun Bu (Laminaria japonica Aresch.) [email protected]
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Magnolol * In this study, Liu et al., (2013) examined the effects of magnolol (Mag), a compound extracted from medicinal herbs, on breast cancer cells in vitro and in vivo. * Highly invasive cancer cells were found to be highly sensitive to treatment. Mag markedly inhibited the activity of highly invasive MDA-‐MB-‐231 cells. Furthermore, Mag significantly downregulated matrix metalloproteinase-‐9 (MMP-‐9) expression, an enzyme critical to tumour invasion. * Mag suppresses tumour invasion by inhibiting MMP-‐9 through the NF-‐κB pathway.
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Scutellaria Barbata * Scutellaria barbata (ban zhi lian) was used in women with metastatic breast cancer (MBC). The trial was an open-‐label, phase 1B, multicenter, dose escalation study. Eligible patients had histologically confirmed breast cancer and measurable stage IV disease. * Investigator assessment classified three patients with stable disease for >120 days (21%). One patient was on Scutellaria barbata for 449 days and remains stable for 700 + days. Independent radiology review identified three patients with objective tumour regression (Perez et al., 2010).
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Objective Tests for TCM Pattern
Pattern Syndrome 证 zhèng
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Genetic Polymorphisms * The genetic mechanisms underlying syndrome differentiation in patients. Twenty-‐nine single nucleotide polymorphisms (SNPs) in EGF, TGFA, and EGFR were investigated. * Two SNPs, rs11466285 in TGFA and rs884225 in EGFR, were significantly associated with the distribution of ZHENG. * The rs11466285 TT genotype increased the risk of damp heat with toxin (DHT) and deficiency of both Qi and yin (DQY) compared with obstruction of blood stasis (OBS).
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Genetic Polymorphisms * The rs884225 AA genotype could increase the risk of DQY and deficiency of both Qi and blood (DQB) compared with yin deficiency due to stomach heat (YDSH). * Parallel comparison among the SNPs and syndrome types revealed that DQB was distinct from YDSH, disharmony between the liver and stomach, stagnation of phlegm muddiness (SPM), OBS, and other syndromes at several SNP loci (Zhang et al., 2013)
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Toxic Heat and Chronic Inflammation
Inflammation
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Medicinal herbs for heat clearance and detoxification (清熱解毒藥) * Artemisia annua (qing hao) * Astragalus membranaceus (huang qi) * Coptidis Rhizoma (huang lian) * Erigeron breviscapus (deng zhan xi xin) * (Houttuynia cordata (yu xing cao) * Oldenlandia diffusa (bai hua she she cao) * Oroxylum indicum (gu zhi hua) [email protected]
* Paeonia suffruticosa (mu dan pi) * Paris polyphylla (zao xiu) * Patrinia scabiosaefolia (bai jiang cao) * Rabdosia rubescens (dong ling cao) * Scutellaria baicalensis (huang qin) * Scutellaria barbata (ban zhi lian) * Solanum nigrum (long kui) * Sophora flavescens (ku shen gen) * Vitex rotundifolia (man jing zi) 126 16/12/14
Chronic Inflammation * About 95% cancer can link modern life style and environment with inflammation as the basic underlying cause (Anand et al., 2008). Chronic or persistent tissue inflammation or irritation is correlated with adverse effects and has long been linked with increasing rate of tumour formation by epidemiological studies (Balkwill & Mantovani, 2001; Rossi & Sawatzky, 2008). * Rudolf Virchow (1821-‐1902) observed frequent cancer origination at the site of chronic irritation. His hypothesis was that some classes of irritants, together with the tissue injury and the ensuing inflammation caused enhanced cell proliferation (Parsonnet, 1999). [email protected]
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Chronic Inflammation * In China in the 7th Century, CE Chao Yuanfang (550-‐630) reported, while working as an imperial physician, “Qi and water stagnation stays in the body, clustering as nodules ('lumps’). Toxic Heat fights Zheng Qi in the body, stagnating and steaming the body, causing hypochondriac pain and fullness.”(Cultural China website) * The Zhu Bing Yuan Hou Lun (Treatise on Causes and Symptoms of Diseases, Vol. 12) was one of the first to mention Toxic Heat in regard to tumours (swellings) (Wong & Wu, 1932).
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Chronic Inflammation * Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases (Blanco et al, 2007). Mediators of the inflammatory response, (e.g. cytokines, free radicals, prostaglandins and growth factors) can induce genetic and epigenetic changes including point mutations in tumour suppressor genes, DNA methylation and post-‐translational modifications and this causes alterations in critical pathways responsible for maintaining the normal cellular homeostasis and leading to the development and progression of cancer (Perwez-‐Hussain & Harris, 2007).
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Chronic Inflammation * In more recent times, Kevin Chan (1995) reports that the source of Toxic Heat is TNF-‐α, IL-‐6 and other inflammatory cytokines, combined with blood stasis, hypoxia and a weakened cellular (Th1) immunity. The concept of Toxic Heat in TCM is central to cancer treatments. * From a more orthodox position, Dalgleish and O’Byrne (2006, p. 5) state, “it is recognised that cancer is a series of stochastic events involving permanent activation of oncogene pathways and deletion of tumour suppressor genes, and in the face of chronic inflammation, immune induction does not occur and the mutated cell survives to divide”. [email protected]
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Chronic Inflammation * The tumour microenvironment consists of tumour, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumour progression and metastasis. * All intimately interact with one another and play an important role in inflammatory and pro-‐angiogenic processes and promote tumor cell proliferation. Interestingly, there is an association between chronic inflammation and tumour development or progression; 15% of all cancers are attributed to inflammatory aetiologies (Kuper, Adami , Trichopoulos, 2000). [email protected]
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Chronic Inflammation * Serum IL-‐6 concentration was significantly higher in patients with breast cancer compared to healthy controls. Serum IL-‐6 level is the most discriminative factor separating healthy controls and the loco-‐regional and metastatic breast cancer patient groups. * These results suggest a role for tumour-‐derived IL-‐6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF (Benoy et al., 2002).
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Oncogenes and Tumour Suppressor Genes * There are two classes of genes that can control cancer development. Oncogenes and tumour suppressor genes belong to one class, while the other class belongs to the caretaker genes. * Healthy cells follow standard rules of growth and proliferation, and have a definitive life span. In contrast, cells with an oncogenic activation undergo much faster cell division with an indefinite life span. Tumour suppressor genes are evolved to inhibit deregulated cell growth.
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NF-‐κB and p53 Antagonise Each Others Activity.
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The yin/yang of NF-‐kB/p53 * Various mediators involved in the pathways are indicated. In addition, p53 and NF-‐ κB can inhibit each other by direct physical interaction through their multimerisation domain. Eventually, the effect of activation NF-‐ κB pathway prevents the activation of p53 pathway and vice versa. KEY: The black coloured upward arrows adjacent to NF-‐ κB and p53 indicate activation of these transcription factors. MDM2: mouse double mute 2; β-‐Tr1: beta transducing repeat containing protein1; ARF: alternate reading frame of INK4/ARF locus; ATR: ATM-‐Rad3 related; CHK: check point kinase; I κB: inhibitor of kB; IKK: inhibitor of kappaB kinase. [email protected]
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NF-‐kB * Coix lachryma-‐jobi (yi ren) seeds is currently the most commonly used treatment for cancer in China and clinical data the use of this preparation of a TCM cancer treatment. Coix seed extract also significantly affects gene expression in cells, including downregulation of genes (such as COX-‐2 and matrixmetalloproteinases) that are considered to be important in neoplasia. * Coix extract inhibits activity of protein kinase C, a major mediator of signal transduction and activator of NF-‐kB (Woo et al., 2005).
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Cancer Stem Cells * The receptor CXCR1 is found on the cancer stem cells and triggers growth of stem cells in response to inflammation and tissue damage. Investigation has suggested an important link between inflammation, tissue damage and breast cancer, which may be mediated by cancer stem cells. * Furthermore, anti-‐inflammatory drugs may provide a means of blocking these interactions, thereby targeting breast cancer stem cells (Wicha 2010). Clearly, inflammation due to immune dysregulation plays a critical role in tumour initiation, progression and metastases.
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Cancer Stem Cells & EMT * Morel et al., (2008) show that cells possessing both stem and tumourigenic characteristics of “cancer stem cells” can be derived from human mammary epithelial cells following the activation of the Ras-‐MAPK pathway. The acquisition of these stem and tumorigenic characters is driven by epithelial-‐ mesenchymal transition (EMT) induction. * Overexpression of MMP-‐9 resulted in induction of the EMT in these cells and this could be reversed by treating with luteolin or quercetin. Co-‐treatment with epidermal growth factor (EGF) plus luteolin or quercetin resulted in a more epithelial-‐like morphology, led to reduced levels of EGF-‐ induced markers of EMT, and caused the restoration of cell– cell junctions (Lin et al., 2011). [email protected]
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TNFα * Tumour necrosis factor-‐alpha (TNFα) has been implicated in both cancer development and progression in some preclinical models. In particular, as a central mediator of inflammation, TNFα might represent one of the molecular links between chronic inflammation and the subsequent development of malignant disease. * Furthermore, deregulated TNFα expression within the tumour microenvironment appears to favour malignant cell tissue invasion, migration and ultimately metastasis formation (Mocellin & Nitti, 2008).
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Inflammatory Cytokines * Tumour initiation, growth and progression and many of these effects are mediated by proinflammatory cytokines. Among these cytokines, the pro-‐tumourogenic function of TNFα, interleukin 6 & 1 (IL-‐6, IL-‐1) is well established (Akira et al., 1990). * Expression patterns of TNFα, IL-‐1beta, IL-‐6 and IL-‐10, along with transforming growth factor beta (TGF-‐β) , were similar in both parental and transformed cells. Considering all these results, we conclude that various cytokines have discrete roles in tumour promotion and cell transformation (Suganuma et al., 2002). [email protected]
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Inflammatory Cytokines * Chronic pathological inflammation is mediated via the continuing presence of a persistent stimulus, such as tumour cells, and the resulting prolonged inflammatory cytokine exposure has the potential to promote tumour growth through the induction of angiogenesis, DNA damage, and other events favourable to tumour invasion and metastases (Balkwill & Mantovani, 2001). Tumours produce their own inflammatory factors. [email protected]
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VEGF * Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. * Elevated VEGF blood concentrations have been proven to be associated with poor prognosis in human neoplasms. This finding is generally explained as a consequence of the potential angiogenic properties of VEGF itself. However, preliminary experimental studies suggest that VEGF, in addition to its angiogenic activity, may also play an immunosuppressant role by inhibiting dendritic cell (DC) maturation (Lissoni et al., 2001). 142 16/12/14
Herbs for Inflammation * Sumu (Lignum Sappan, 苏⽊木) was first mentioned in Xin Xiu Ben Cao (Newly Revised Materia Medica) by Su Jing in 657-‐659 CE and its action are said to ‘activate Blood’, ‘open channels and relieve pain’. * The aqueous extract of Lignum sappan (AELS) may markedly decrease the level of TNF and IL-‐6 (Wang et al 2007), it has also been shown it can kill cancer cell lines of HL-‐60, K562, L929 and Yac-‐1 at the concentration of 2μl/ml in vitro. The survival time of mice treated with AELS is increased by 185% (P0.01) by ip 0.2ml/mouse×7d (Ren & Zhang 1990).
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Herbs for Inflammation * Radix Pulsatillae (bai tou weng) use goes back to the Shen Nong Ben Cao Jing (2nd CE) and is said to ‘clear Heat’ and ‘eliminate Toxin’. It strongly inhibits the secretion of TNF, IL-‐1 and IL-‐6 from Kupffer cells [KC] stimulated by Lipopolysaccharide [LPS] (Hu et al, 2010). * Xian and Qian (2009) state that bai tou weng is an “innovative antitumour-‐drug of high effect and low toxin”. Triterpenoid Saponins isolated from Pullsatilla Root appear to be an important promoiety for the enhancement of anticancer activity of their aglycones (Bang et al 2007).
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Herbs for Inflammation * Herba Portulacae oleracea (ma chi xian) may act on adipose cells damaged by the high lipid serum to increase cell viability and lower the levels of TNF-‐α and IL-‐6 secreted by adipose cell secreted (Xiao et al, 2005). Its use is first mentioned in Xin Xiu Ben Cao and is said to ‘clear Heat’ and ‘eliminate toxin’ and also ‘cools Blood’ and stops bleeding. * Supernatant TNF-‐α and IL-‐6 decrease significantly after Phytolacca acinosa (shang lu decoction) culture (Zhang et al, 2004) while Chrysanthemum indicum (ye ju hua) has an inhibitory effect on sIL-‐2R, IL-‐6 and TNF-‐α (Zhang et al, 2000).
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Herbs for Inflammation * The serum levels of TNF-‐α, IL-‐6 and IL-‐10 decrease following baicalin treatment (Liu et al 2006). The flavonoid baicalin, isolated from the dried root of Scutellaria baicalensis (huang qin) is widely used in the traditional Chinese herbal medicine for its anti-‐inflammatory, anti-‐pyretic and anti-‐hypersensitivity effects. * Apoptosis was enhanced by the combination treatment of baicalin and baicalein, which activated caspases-‐3 and caspase-‐9, downregulated the level of bcl-‐2 and upregulated the level of bax or p53 via the ERK/p38 MAPK pathway (Zhou et al., 2009). [email protected]
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Herbs for Inflammation * Baicalin with scutellarin (both from Scutellaria baicalensis), and two extracts purified from Salvia miltiorrhiza (dan shen) (SM-‐470, circulatory stimulant) and Camellia sinensis (Cam-‐300, antipyretic), and examined their anti-‐proliferation effects on the human breast cancer cell lines MCF-‐7 and T-‐47D. * All four compounds inhibited MCF-‐7 and T-‐47D cell proliferation, SM-‐470, Cam-‐300, scutellarin and baicalin inhibited the proliferation of human breast cancer cells as well as CAL-‐27 and FaDu cells (Franek et al., 2005).
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Herbs for Inflammation * Daidzein treatment resulted in decreases in cyclin D, CDK2, and CDK4, whereas the expression of CDK6 and cyclin E was unchanged. Daidzein treatment increased the expression of the CDK inhibitors p21Cip1 and p57Kip2. Thus, daidzein exerts its anticancer effects in human breast cancer cells via cell cycle arrest at the G1 and G2/M phases (Peterson & Barnes, 1991). * The isoflavones daidzein and genistein inhibited iNOS protein and mRNA expression and also NO production in a dose-‐ dependent manner. The results explain the pharmacological efficacy of flavonoids as anti-‐inflammatory compounds (Hämäläinen et al., 2007). [email protected]
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Celprotect * Radix Pueraria lobata (Ge Gen) (standardised Daidzein) * Semen Sojae Praeparatum (Dan Dou Chi) (standardised Glycitein) [Note: this methoxyisoflavone is GMO free] * Genista tinctoria (ran liao mu) (extract Genistein 99%) * Radix Scutellariae Baicalensis (Huang Qin) (standardised Baicalein) * Radix Scutellariae Baicalensis (Huang Qin) (standardised Baicalin) * Fructus Gardeniae Jasminoidis (Zhi Zi) (standardised Jasminoidin) [email protected]
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ICC
(Inflammation Control Compound) * Radix Stephania tetrandra (fen fang ji) contains extract 15% Tetrandrine, 5% Fangchinoline * Folium Urticae dioica extract * Folium Ocimum sanctum contains extract 2.5% Ursolic acid * Radix Zingiber officinale (sheng jiang) contains extract 20% gingerols * Gum Boswellia serrata contains extract 30% AKBA * EGCG * Terminalia chebulla (he zi) contains 150 extract Luteolin 90%
* Reduces various inflammatory mediators, including interleukin-‐6 (IL-‐6), IL-‐1 beta, TNF-‐α, prostaglandin E2 and leukotrienes. * Rare side-‐effects may include diarrhoea, skin rash, acid reflux and nausea and may be contraindicated in those with pre-‐existing gastritis or gastro-‐oesophagael reflux disease (GORD). 16/12/14
Luteolin * Luteolin, a plant-‐derived flavonoid, is thought to inhibit tumour growth due to its strong inhibitory effect on nuclear factor (NF)-‐κB. * Results suggest that AMPK activity is critical for the inhibition of cancer cell growth, possibly via modulation of NF-‐κB activity. Hwang et al., (2011) showed that luteolin treatment causes the release of reactive oxygen species (ROS) and that these intracellular ROS in turn mediate AMPK-‐NF-‐κB signalling in cancer cells. * Having multiple biological effects such as anti-‐inflammation, anti-‐allergy and anticancer, luteolin functions as either an antioxidant or a pro-‐oxidant biochemically (Yin et al., 2008). [email protected]
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Cryptotanshinone * Cryptotanshinone (CTSO) is a major constituent of tanshinones, which are extracted from the medicinal herb Salvia miltiorrhiza (dan shen) and have well-‐documented anti-‐ oxidative and anti-‐inflammatory effects. * CTSO can reduce prostaglandin E2 synthesis and reactive oxygen species generation catalysed by COX-‐2, without influencing COX-‐1, and is directed against enzymatic activity of COX-‐2 (Jin et al. 2006).
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Tanshinone IIA * Tanshinone IIA (Tan IIA) could serve as a potential selective oestrogen receptor modulator (SERM) to treat inflammation without increasing the risk of breast cancer. It exerts anti-‐ inflammatory effects by inhibition of iNOS gene expression and NO production, as well as inhibition of inflammatory cytokines IL-‐1β, IL-‐6, and TNF-‐α (Fan et al., 2009). * Tan IIA could also decrease the expression of TNF-‐α and activation of nuclear transcription factor-‐kappa B (NF-‐κB) (Ren et al., 2010)
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Panaxea Tanshins * Salvia Miltiorrhiza (contains extract Tanshinone IIA and Cryptotanshinone) Note: * TANSHINS significantly increase the activity of CYP1A2 in a dose-‐dependent manner. CTS can induce hepatic microsome CYP1A2 expression significantly, which indicates potential drug-‐drug interaction might occur when CTS is co-‐ istrated with those drugs metabolised by CYP1A2 such as Capecitabine / Capecitabine (Xeloda), Lapatinib / Lapatinib (Tykerb) * Long term use may increase DHEA-‐S [email protected]
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Blood Stasis
Coagulation Factors
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Blood Stasis * Drugs with the efficacy of modifying rheological properties of blood, blood vessels and their interactions are denoted by “haemorheologicals”. Drugs of anti-‐hyperviscosaemia, anti-‐ coagulants, anti-‐platelet drugs, anti-‐thrombotics, vasodilators, endothelial cell protectors and anti-‐arthrosclerosis should be considered as haemorheologicals due to the actions in keeping blood fliudity and in maintaining normal vascular functions. * Haemorheologicals are importance for and ageing and life-‐ threatening diseases. ‘Blood Stasis’ syndrome is a common pathological syndrome in the elderly. In traditional Chinese medicine, the treatment for the syndrome is by herbs which activates blood circulation to remove ‘Blood Stasis’ (Liao , 156 16/12/14 2000).
Blood Stasis * Clot formation on the tumour cells facilitates tumour cell spreading, improving the attachment to the endothelium and enhancing tumour cell survival and metastasis (Im et al., 2004). Platelets surrounding tumour cells release growth factors and chemokines (VEGF, ILGF1, TGF-‐β) that enhance tumour cell proliferation and angiogenesis (Gay & Felding-‐Habermann., 2011). * Direct interaction between platelets and tumour cells triggers Epithelial to mesenchymal transition (EMT) through platelet derived TGF-‐β/SMAD and NF-‐κB pathways (Labelle et al., 2011). Multiple mechanisms have the potential to contribute to metastasis enhancement by coagulation and platelet 16/12/14 aggregation by tumour cells. 157
Blood Stasis & NK Cells * The idea of using ‘immune tonics’ may be a fruitless pursuit. * The aggregation of platelets around tumour cells in tissue culture greatly diminishes the ability of Natural Killer (NK) cells to lyse cancer cells in culture (Bobek et al, 2005). * Consistent with these findings, activation of platelets and the presence of fibrinogen have been shown to help tumour cells to evade immune surveillance mechanisms, protecting them from killing by NK cells (Palumbo et al, 2005, 2007), by both physical means and through signalling that leads to NK quiescence (Stewart, Vivier & Colonna, 2006; Kopp, Placke & Salih, 2009). [email protected]
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Blood Stasis * Chinese herbal medicine contributes a great deal to the health of the Chinese nation. Blood stasis syndrome (BSS) is a significant pathological syndrome in TCM. * The approach of treatment for BSS is activating blood circulation to remove blood stasis (ABCRBS). Herbs of ABCRBS are a category of over 10% in the modern Chinese Pharmacopoeia (Volume I – Herbal Medicine volume). Medicinal for promoting blood circulation and eliminating stasis in cancer (活⾎血化瘀藥) * * * * * *
Curcumae longae (jiang huang) Curcumae wenyujin (yu jin) Leonurus japonicus (yi mu cao) Panax notoginseng (san qi) Rheum officinale (da huang) Salvia miltiorrhiza (dan shen)
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Achyranthes Longifolia (tu niu xi) Squama Manis (chuan shan jia) Caulis Spatholobu (ji xue teng) Rhizoma Sparganii (san leng) Rhizoma Curcumae (e zhu) Eupolyphaga (di bie chong)
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Pro Creation R Capsules * Radix Angelica sinensis (dang gui) * Radix Ligusticum wallichii (chuan xiong) * Radix Salvia miltiorrhiza (dan shen) * Semen Prunus persicae (tao ren) * Fructus Liquidamber taiwaniani (lu lu tong) * Fructus Gleditsia sinensis (zao jiao) * Radix Saussurea lappa (mu xiang) * Radix Paeonia lactiflora (chi shao) * Rhizoma Corydalis (yan hu suo) * Frucus Melia toosendan (chuan Lian zi) * Radix Bupleurum chinense (chai hu) [email protected]
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Blood Stasis Formulations * Xiongshao capsule: Rhizoma Ligustici Chuanxiong, Radix Paeoniae Rubrae (chi shao) * Taohongsiwu decoction: Semen Persicae (tao ren), Flos Carthami (hong hua), Rhizoma Ligustici Chuanxiong, Radix Angelica sinensis (dang gui), Radix Paeoniae Alba (bai shao), Radix Rehmanniae Praeparata (shu di) * Xue Fu Zhu Yu Tang: Semen Pruni Persicae (tao ren), Radix Ligustici Chuanxiong, Flos Carthami Tinctorii (hong hua), Radix Angelicae Sinensis (dang gui), Radix Paeoniae Rubrae (chi shao), Radix Cyathulae Officinalis (chuan niu xi), Radix Rehmanniae Glutinosae (sheng di), Radix Bupleuri (chai hu), Radix Platycodi Grandiflori (jie geng), Fructus Citri Aurantii (zhi 161 16/12/14 ke), Radix Glycyrrhizae Uralensis (gan cao)
Panaxea Blood Stasis Granule * Buyanghuanwu (BYHW) Granules: Radix Astragalus (huang qi), Semen Persicae (tao ren), Flos Carthami (hong hua), Rhizoma Ligustici Chuanxiong, Radix Angelica sinensis (dang gui), Radix Paeoniae Rubrae (chi shao), Pheretima / earthworm (di long) (All above: Liu et al., 2012) * BYHW is an historical and empirical formula that is now being researched extensively in China. This research includes cardiovascular system diseases including DVT, spinal injuries, motor and nervous system diseases including migraine, metabolic diseases, respiratory and digestive diseases, and cancer (see Panaxea research database). [email protected]
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ji xue teng * The Chinese herb Spatholobus suberectus (ji xue teng) is commonly prescribed to cancer patients. In this study, the anti-‐cancer effect of SS and its molecular mechanisms have been investigated. Cell growth assay showed that SS effectively inhibits tumour cell growth in a dose-‐dependent manner and experiments show that the efficiency of SS alone group was superior to docetaxel or to docetaxel and SS combined. * SS is a potential herb for cancer treatment by inhibiting tumour growth via induction of apoptosis and arrest of the cell cycle at G2/M phase (Wang et al., 2011). [email protected]
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Oridonin * Rabdosia rubescens (dong ling cao) is a Chinese medicinal herb used widely. The aerial parts of RR and other species of the same genus has been reported to have the functions of clearing “heat” and “toxicity”, nourishing “yin”, removing “blood stasis”, and relieving swelling (Tang & Eisenbrand, 1992). * RR and its extracts have been shown to be able to suppress disease progress, reduce tumour burden, alleviate syndrome and prolong survival in patients (Henan Medical Institute, 1978) * Oridonin, was isolated from RR and was shown to be a potent apoptosis inducer in a variety of cancer cells (Fujita et al., 1988; Zhou et al., 2007) 164
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Panaxea OriJi * Oridonin extract 40% * Supercritical extract of Spatholobus suberectus 60%
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Fibrosis * Fibrotic disorders of the liver, kidney and lung are associated with excessive deposition of extracellular matrix proteins and on-‐going coagulation-‐cascade activity. In addition to their critical roles in blood coagulation, thrombin and the immediate upstream coagulation proteases, Factors Xa and VIIa, influence numerous cellular responses that may play critical roles in subsequent inflammatory and tissue repair processes in vascular and extravascular compartments. * Coagulation proteases have also been shown to play a role in the pathogenesis of fibrosis (Chambers & Laurent, 2002).
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Fibrosis * Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Plasminogen activator inhibitor-‐1 (PAI-‐1) is a key serpin (Yuko et al., 2008). * Proteolytic degradation of extracellular matrix (ECM) components during tissue remodeling plays a pivotal role in normal and pathological processes including wound healing, inflammation, tumour invasion, and metastasis (Park et al., 1999). * Protease inhibitors are emerging as potentially therapeutic tools to treat cancer (DeClerck & Imren, 1994). [email protected]
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Fy)Brox * Quercetin (Flos Sophorae extract) * Baicalein Scutellaria baicalensis extract) * Baicalin (Scutellaria baicalensis extract) * Salvianolic Acid B (Salvia Miltiorrhiza extract) * Emodin (Rheum Palmatum extract) * Scutellaria Baicalensis (huang qin) * Salvia Miltiorrhiza (dan shen) * Rheum Palmatum (da huang)
* Anti-‐fibrotic in total collagen accumulation * Anti-‐nodule formation * ‘Blood Buster’ * Fibrosis, characterised by extracellular matrix (ECM) accumulation and disruption of normal tissue architecture, is the common cause of chronic failure of many organs 168
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Congested Interstitial Fluid & the Extracellular Matrix
Phlegm Damp
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Phlegm Damp * The phlegm-‐dampness constitution is one of the nine constitutions and is the most common type in constitution study. Genomics studies found four upregulated genes: COPS8, GNPDA1, CD52 and ARPC3; and six downregulated genes: GSPT2, CACNB2, FLJ20584, UXS1, IL21R and TNPO in the phlegm-‐dampness constitution. * Gene functional analyses on genes affecting the differences between the phlegm-‐dampness constitution and the balanced constitution indicated that people with phlegm-‐dampness have a much higher risk of obesity, metabolic syndrome, hypertension, hyperlipaemia and diabetes (Wang et al., 2013). [email protected]
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Phlegm Damp * E-‐cadherin (E-‐cad) is a subclass of the cadherin family that plays a major role in maintenance of intercellular junctions in epithelial tissues (Oka et al., 1993). * There is a significant difference in E-‐cad expression between the stagnation of phlegm-‐damp type and the deficiency in both qi and blood and the deficiency-‐cold of stomach and spleen types, where E-‐cad expression was high. * E-‐cad expression is relatively low in the internal obstruction of stagnant toxin type and the in-‐coordination between liver and stomach type, where tumour development and metastasis may be associated with low E-‐cad expression, or with low homogeneous adhesiveness between tumour cells (Sun et al., 2007). 171
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Phlegm Damp * It is suggested that cell dissociation in tumours is accomplished by loss of function or expression of the epithelial cell adhesion molecule E-‐cadherin, and through the activity of cell motility factors, like scatter factor. * A striking feature of metastatic cells is the considerable flexibility in their adhesive interactions with other cells or components of the extracellular matrix (Behrens, 1993). * Oka et al., (1993) found significant correlations between E-‐cad expression and clinicopathological features. The frequency of reduced E-‐cadherin expression (Rd type) was significantly higher in invasive ductal carcinomas (58%) and poorly differentiated carcinomas (84%) than in noninvasive and well-‐ 16/12/14 differentiated carcinomas. 172
Phlegm Damp * The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. * ECM is commonly deregulated and becomes disorganised in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis (Lu, Weaver, Werb, 2012). * A direct link between hypoxia and the composition and the organisation of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome (Gilkes, Semenza, Wirtz, 2014). 173 16/12/14
Phlegm Damp * Interactions between the cell and the ECM are critical in controlling the fate and behaviour of cancer cells. Alterations in either the ECM or in cellular events affect this interaction. give an overview of the role of cell–ECM interactions in cancer, with a particular focus on the reciprocal nature of the cell–ECM interactions and how this contributes to cancer progression (van Dijk, Göransson, Strömblad, 2013). * Fibrillar collagens, fibronectin, hyaluronan and matricellular proteins are matrix components that are common to both involution and cancer. Moreover, some of these proteins have in recent years been identified as important constituents of metastatic niches in breast cancer (Oskarsson, 2013). 174
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Phlegm Damp * Much of the mass of a solid tumour is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumourigenic processes. * One of the processes that is vital to tumour growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro-‐ and antiangiogenic factors that control tumour angiogenesis in a tightly regulated fashion (Campbell et al., 2010). 175
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Cell Adhesion Molecules * Cell adhesion molecules (CAMs) are proteins located on the cell surface involved in binding with other cells or with the extracellular matrix (ECM) in the process called cell adhesion. * Integrins, one of the major classes of receptors within the ECM, mediates cell-‐ECM interactions with collagen, fibrinogen, fibronectin, and vitronectin. Integrins provide essential links between the extracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such as apoptosis, differentiation, survival, and transcription. * The extracellular domain has major repeats called extracellular cadherin domains. Sequences involved in Ca2+ binding between the ECDs are necessary for cell adhesion. [email protected]
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ECM
* In biology, the extracellular matrix (ECM) is a collection of extracellular molecules secreted by cells that provides structural and biochemical to the surrounding cells. * Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-‐to-‐cell communication and differentiation are common functions of the ECM (Abedin & King, 2010) [email protected]
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Interstitial Fluid * Interstitial fluid is a solution that bathes and surrounds the cells of multicellular animals. It is the main component of the extracellular fluid, which also includes plasma and transcellular fluid. The interstitial fluid is found in the interstitial spaces, also known as the tissue spaces. * Interstitial fluid bathes the cells of the tissues. This provides a means of delivering materials to the cells, intercellular communication, as well as removal of metabolic waste. * Extravascular or interstitial factors may contribute significantly to the inflammatory process including production of IL-‐6(doi: 10.1113/jphysiol.2011.206136) [email protected]
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Interstitium * The interstitium or interstitial space describes the space outside the blood and lymphatic vessels. It contains two phases; the interstitial fluid (IF) and the extracellular matrix. It consists of a solid or matrix phase and a fluid phase (Gel/ Sol) together constituting the tissue microenvironment. * Accumulated data show that tumour interstitial fluid (IF) is hypoxic and acidic compared with subcutaneous IF and plasma, and that there are gradients between IF and plasma giving information on where substances are produced and thereby reflecting the local microenvironment.
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Phlegm Damp * Is Phlegm Damp or hidden phlegm a disregulation of fluids and the attendant components? * Among the several different forms of cell interactions known to exist in multicellular organisms intercellular communication provides the most direct form of communication by allowing free exchange of ions and small molecules between neighbouring cells via permeable membrane junctions. This type of communication has been implicated in various biological functions such as cell differentiation, embryonic development, and tissue growth regulation (Azarnia & Larsen, 1977). * There is a significance in cell junction dysregulation in cancer. [email protected]
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MMTV-‐Wnt-‐1
Mammary Tumour Virus
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MMTV-‐Wnt-‐1 * In human breast cancers, a phenotypically distinct minority population of tumourigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumour growth. Studies suggest that there is a cancer stem cell compartment in the MMTV-‐Wnt-‐1 breast tumours (Cho et al., 2008). * The expression of the Wnt-‐1 proto-‐oncogene can induce mammary hyperplasia and tumourigenesis in the absence of ERα in females and in males.
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Ursolic Acid * All ursolic acid (UA) doses decreased tumour cell proliferation and UA at 0.10% mg/kg body weight/day was most effective in inhibiting tumour take and decreasing final tumour size. Modulation of Akt/mTOR signalling and induction of apoptosis appeared to mediate these effects on tumour growth. * UA potently disrupted cell cycle progression and induced necrosis in a clonal MMTV-‐Wnt-‐1 mammary tumour cell line in vitro. This study s the potential of UA as an anti-‐ tumourigenic agent (De Angel et al., 2010).
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Stage 0 Pre-‐cancerous lesions
DCIS & LCIS
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DCIS * Ductal carcinoma in situ (DCIS) is encountered much more frequently in the screening population compared to the symptomatic setting. The behaviour of DCIS is highly variable and this presents difficulties in choosing appropriate treatment strategies for individual cases. DCIS s for 5 to 20% of ‘cancers’. * Untreated, up to 50% of DCIS lesions progress to invasive disease, and that the time for progression may be up to four decades (Saunders et al, 2005; Collins et al., 2005). * Ten years after DCIS diagnosis, 98% to 99% of women will be alive. [email protected]
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DCIS Interventions * The natural history of DCIS remains to be elucidated, and it is unclear whether all DCIS cases progress to invasive breast cancer. Surgery plus radiation therapy or mastectomy is recommended for women in whom this potentially non-‐ progressive cancer is detected. * Regina Dehen (2013) s the developing trend toward active surveillance in lieu of breast-‐disfiguring surgery and offers evidence that CAM therapies including herbs and acupuncture may be of value in preventing progression of DCIS to invasive breast cancer.
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DCIS Interventions * Yanghe Huayan Decoction (YHD) Cornu Cervi Degelatinatium (lu jiao shuang) 12 g, prepared rhizome of rehmannia (shu di) 9 g, Cortex Cinnamomi (rou gui) 6 g, Semen Sinapis (bai jie zi) 3 g, Radix Curcumae (yu jin) 12 g, Psuedobulbus Cremastrae (shan ci gu) 15 g, Bulbus Frittillariae Thunbergii (zhe bei mu) 9 g, licorice root (gan cao) 6 g at the daily dose of 7.2 g/kg. * YHD could partially inhibit and reverse canceration of DCIS. It also could inhibit ki67 protein and mRNA expression. Its effect was similar to tamoxifen. * It is suitable for prevention and treatment of precancerous lesions of breast cancer (Li et al., 2014). 187
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Panaxea Cruciferous * DIM is a new class of ERβ-‐selective compounds, because it does not bind to ERβ, but instead it selectively recruits ERβ and co-‐activators (Vivar et al, 2010) * DIM can induce apoptosis in breast cancer cells independent of oestrogen receptor status by a process that is mediated by the modulated expression of the Bax/Bcl-‐2 family of apoptotic regulatory factors (Biochemical Pharmacology 2002). * I3C acts through a pathway that is distinct from either DIM or tamoxifen in regulating CDK2 enzymatic activity (The Journal of Biological Chemistry 2005). [email protected]
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Panaxea Cruciferous * DIM-‐treated subjects, relative to placebo, showed a significant increase in levels of 2-‐OHE1, DIM, and cortisol, and a non-‐ significant increase of 47% in the 2-‐OHE1/16alpha-‐OHE1 ratio from 1.46 to 2.14. In this pilot study, DIM increased the 2-‐ hydroxylation of oestrogen urinary metabolites (Dalessandri et al., 2004). * Results of a study by Nicastro et al., (2013) demonstrate the important role of hepatocyte growth factor (HGF) and c-‐Met (also called hepatocyte growth factor receptor) in DIM's anti-‐ proliferative effect on breast cancer cells and suggest that DIM could have preventive or clinical value as an inhibitor of c-‐ Met signalling. [email protected]
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Empirical and Researched Formulas
Breast Cancer Granules for Stages
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Stages * Breast cancer staging using the TNM system is based on the size of the tumour (T), whether or not the tumour has spread to the lymph nodes (N) in the armpits, and whether the tumour has metastasised (M). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. The main stages are: * Stage 0 is a pre-‐cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). * Stages 1–3 are within the breast or regional lymph nodes. * Stage 4 is 'metastatic' cancer that has a less favourable prognosis (NCI: accessed Aug 2014). * The difference between the two classifications of grade and stage is that the former views the status from pathology and the latter views it from the cancer cell migration. [email protected]
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Stages Stage
5 Year Survival
DCIS
93%
I
88%
IIA
81%
IIB
74%
IIIA
67%
IIIB
41%
IIIC
49%
IV
15%
Younger women tend to have a poorer prognosis than post-‐menopausal women due to several factors. Their breasts may change with their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts. There may also be biologic factors including greater inflammatory factors contributing to a higher risk of disease recurrence for younger women 16/12/14 with breast cancer (Peppercorn, 2009).
Empirical Formulas Cancer courses
Before operation 1. Liver Qi depression and phlegm stasis syndrome: Tiao Shen Gong Jian Tan 2. Turbid phlegm and blood stasis: Xue Yu Zhu Yu Tang and/or Xiao Yao Lou Bei San 3. Chong-‐Ren imbalance syndrome: Er Xian Tang. 4. Deficiency of the vital principle and poison blazing: Ba Zhen Tang w/ sheng di, mu dan pi, qing dai, shui niu jiao (ban mao, chan su) TCM indications and Chinese herbs (Lin et al., 2006) [email protected]
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Empirical Formulas Cancer courses
After operation 1. Syndrome of incoordination between spleen and stomach: Si Jun Zi Tang (not with ER+ tumours) 2. Two deficiency syndrome of Qi and blood (Yin): Ba Zhen Tang w/ mai dong, nu zhen zu (not with ER+ tumours) 3. Qi deficiency and blood stasis: Yi Qi Huo Xue Tang Period of consolidation 1. Two deficiency syndrome of Qi and blood (Yin): Yi Qi Yang Rong Tang 2. Deficiency of spleen and kidney: Jin Kui Shen Qi Wan 3. Chong-‐Ren imbalance syndrome: Er Xian Tang [email protected]
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Breast Cancer Stage 1
Pattern: Phlegm and qi Stagnation * Radix Angelicae Sinensis (dang gui) * Radix Paeoniae Lactiflorae (bai shao) * Radix Pseudostellariae (tai zi shen) * Sclerotium Poriae Cocos (fu ling) * Radix Bupleuri (chai hu) * Pericarpium Citri Reticulatae (chen pi) * Semen Trichosanthis (gua lou ren) * Bulbus Fritiliariae Cirrhosae (chuan bei mu) * Tuber Curcumae (yu jin) * Spica Prunellae Vulgaris (xia cu cao) * Rhizoma Iphigeniae Indicae (shan ci gu) [email protected]
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Breast Cancer Stage 2 & 3 Pattern: Heat and Blood Stasis
* Herba Taraxaci Mongolici cum Rd (pu gong ying) * Herba Solani Nigri -‐ Long Kui * Radix Arnebiae seu Lithospermi -‐ Zi Cao * Spica Prunellae Vulgaris -‐ Xia Ku Cao * Radix Trichosanthis Kirilowii -‐ Tian Hua Fen * Semen Vaccariae Segetalis -‐ Wang Bu Liu Xing * Pericarpium Citri Reticulatae Viridae -‐ Qing Pi * Bulbus Fritillariae Thunbergii -‐ Zhe Bei Mu * Radix Bupleuri -‐ Chai Hu * Fructus Viticis -‐ Man Jing Zi [email protected]
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Breast Cancer Stage 4
Pattern: Toxic Heat and qi & yin Deficiency * * * * * * * * * * * * *
Flos Lonicerae Japonicae -‐ Jin Yin Hua Herba Taraxaci Mongolici cum Rd -‐ Pu Gong Ying Rhizoma Paridis -‐ Zao Xiu Herba Scutellariae Barbatae -‐ Ban Zhi Lian Radix Rehmanniae Glutinosae -‐ Sheng Di Tuber Ophiopogonis Japonici -‐ Mai Men Dong Herba Dendrobii -‐ Shi Hu Radix Scrophulariae Ningpoensis -‐ Xuan Shen Radix Hibiscus -‐ Fu Rong Sclerotium Poriae Cocos -‐ Fu Ling Radix Pseudostellariae -‐ Tai Zi Shen Radix Astragali Membranacei -‐ Huang Qi Herba Gynostemma pentaphyllum -‐ Jiao Gu Lan
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Tests * Hyper coagulation: Fibrinogen, D-‐Dimer, Anti-‐thrombin III, and Plasminogen Activator Inhibitor 1 (PAI-‐1) and uPA * Tissue Factor (TF) and Blood Coagulation * Inflammation: C-‐reactive Protein, ESR (SED rate), IL-‐6 and TNFα, Serum amyloid A * Markers of Angiogenesis: Vascular Endothelial Growth Factor (VEGF), Interleukin (IL)-‐ 8, cathepsin B, Survivin, Matrix Metalloproteinases (MMP)-‐2 and 9, HIF-‐1a, Hepatocyte Growth Factor (HGF), epidermal growth factor (EGF) and its receptor EGFR, Fibroblast Growth Factor-‐2 (FGF-‐2) * Melatonin [email protected]
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Chemo, Radiotherapy, Tamoxifen & SEEMs, Immune Function, Aerobic Glycolysis, MDR
Additional Protocols
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Panaxea A1 Mark II * Angiogenesis is an essential event during the excessive growth and metastatic spread of solid tumours. Anti-‐angiogenic agents have become a new choice of therapy for patients with cancer. * In this study, Jiang et al., (2012) investigated the potential effect of Yangzheng Xiaoji (A1-‐ Mark2), a traditional Chinese medicinal formula presently used in the treatment of several solid tumours on angiogenesis. * It markedly inhibited in vitro tubule formation from vascular endothelial cells. They demonstrated that the extract has a concentration-‐dependent inhibitory effect on cell-‐matrix adhesion and cellular migration (Ye et al., 2012). [email protected]
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A1 Mark II * Radix Astragali (huang qi) * Fructus Ligustri Lucidi (nu zhen zi) * Radix Ginseng (ren shen) * Rhizoma Curcumae Ezhu (e zhu) * Fructificatio Ganodermatus (ling zhi) * Herba Gynostemma pentaphyllum (jiao gu lan) * Rhizoma Atractylodis Macrocephalae (bai zhu) * Herba Scutellariae Barbatae (ban zhi lian)
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A1 Mark II (continued)
* Herba Hedyotiolis Diffusae (bai hua she she cao) * Sclerotium Poriae Cocos (fu ling) * Eupolyphaga sinensis (di bie chong) * Endothelium Corneum Gigeriae Galli (ji nei jin) * Duchesnea indica (She Mei) * Herba Solani Lyrati (shu yang quan) * Herba Artemisiae Capillaris (yin chen Hao) * Radix Cynanchi Paniculatii (xu chang qing)
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Protocols Pre-‐chemo, radiotherapy and surgery * Strengthen qi and Blood * Clear qi Stagnation and Blood Stasis * Clear Phlegm * Clear Toxic Heat Concurrent to chemotherapy * Protect Essence & Warm Channels * Clear Toxins * Protect qi
Concurrent to radiotherapy * Protect yin & Fluids * Clear Heat Toxin Post chemo and radiotherapy * Tonify qi, Blood, yin / yang * Gently move qi and Blood
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Panaxea Chem1 Caps * Radix Panax ginseng (ren shen) * Radix Atractylodes macrocephala (bai zhu) * Rhizoma Dioscoreae (shan yao) * Root Inula helenium (tu mu xiang) ⼟土⽊木⾹香 * Pericarpium Citrus aurantium (zhi ke) [email protected]
* Fructus Amomum villosum (sha ren) * Radix Astragalus membranaceus (huang qi) * Semen Ziziphus jujuba var. spinosa (suan zao ren) * Radix Polygala tenuifolia (yuan zhi) * Radix Coptis chinensis (huang lian) * Radix Panacis Quinquefolii (xi yang shen) 204 16/12/14
Panaxea Chem1 Caps * Chem 1 caps has been found to have a number of effects on both innate and adaptive immune processes, with potential indirect anticancer activity in in vivo studies. No side effects were observed treated with the botanical compound, and no negative effects were observed on the response to chemotherapy or tumour mass. * No toxic effects were attributed by patients to the Chem 1 caps treatment, and 85% reported that they believed the botanical compound had helped reduce symptoms of breast cancer chemotherapy treatment (Rachmut et al., 2013).
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Panaxea CTF
(Chemotherapy Granules) * Radix Ginseng (ren shen) * Radix Codonopsis Pilosulae (dang shen) * Radix Astragali Membranacei (huang qi) * Radix Angelicae Sinensis (dang gui) * Folium Dichroae Febrifugae (shu di) * Radix Polygoni Multiflori – (he shou wu) * Gelatinum Corii Asini – (e jiao) * Fructus Lycii (gou qi zi) * Caulis Millettiae Reticulatae (ji xue teng) * Tuber Ophiopogonis Japonici (mai men dong) * Rhizoma Polygonati (huang jing) * Herba Leonuri Heterophylli (206 yi mu cao)
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Panaxea
CTF (Chemotherapy Granules)
(continued)
* Fructus Ligustri Lucidi (nu zhen zi) * Herba Dendrobii (shi hu) * Mori Albae Fructus (sang shen) * Herba Epimedii (yin yang huo) * Semen Cuscutae Chinensis (tu si zi) * Fructus Psoraleae Corylifoliae (bu gu zhi) * Sclerotium Cordyceps Chinensis (dong chong xia cao) * Herba Cynomorii Songarici (suo yang) * Fructus Alpiniae Oxyphyllae (yi zhi ren) * Radix Morindae Officinalis (ba ji tian) * Cortex Eucommiae Ulmoidis (du zhong) * Radix Salviae Miltiorrhizae (dan shen) 207
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Warburg Effect * Aerobic glycolysis is inefficient from the standpoint of ATP production, but it provides cancer cells with biomolecules implicated in the synthesis of lipids and nucleotides required for cellular proliferation. Thus, targeting aerobic glycolysis has clearly been recognized as a potentially fruitful approach for the treatment of cancer. * The inhibition of aerobic glycolysis by a combination of alpha lipoic acid and hydroxycitrate in Panaxea Synsergize effectively inhibits tumour development (Baronzio et al., 2012) Ingredients: * Alpha Lipoic Acid Hydroxycitric Acid 160 grams Powder Silica [email protected]
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Panaxea Synsergize * Eleven patients with advanced metastatic cancer from were treated with per os 0.4 to 1.8 g of lipoic acid and 1.2 to 3 g of hydroxycitrate during 2 to 21 months in addition to their normal chemotherapeutic regimen. Side effects occurred in half of the patients but were mild (grade 1-‐3) and limited to gastrointestinal disorders that disappeared on using proton pump inhibitors or decreasing the doses. Five patients were characterised by a partial regression, 3 by a stable disease, and 3 by disease progression. * Most of the patients receiving treatment for more than 6 months displayed partial regression or stabilisation. In conclusion Baronzio et al., (2012) found the results from these preliminary treatments that Synsergize can be used safely with various common standard chemotherapeutic regimens. [email protected]
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Panaxea MEGA EGCH * Additive and synergistic effects of EGCG when combined with conventional cancer therapies have been proposed, and its anti-‐inflammatory and antioxidant activities have been related to amelioration of cancer therapy side effects (Lecumberri et al., 2013). * Most cancers are believed to be initiated from and maintained by a small population of cancer stem-‐like cells (CSC) or tumour-‐initiating cells (TIC) that are responsible for tumour relapse and chemotherapeutic resistance. EGCG, the most abundant catechin in green tea, has been reported to induce growth inhibition and apoptosis in some cancer cells (Lin et al., 2012). [email protected]
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Chemotherapy Compounds * Coenzyme Q10 and L-‐Carnitine protect the heart * Vitamin E, L-‐Glutamine and B6 are neuro-‐protective * Omega 3 for Cachexia * Melatonin and IM1 mushroom extract protect the immune system * Coenzyme Q10 and multi-‐vitamin / mineral help with fatigue * Vitamin D3 is a chemotherapy agonist * Alpha Lipoic Acid is neuro-‐protective
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Panaxea RTF (Radiotherapy)
Heat and Dampness with yin & qi Deficiency * Herba Hedyotiolis Diffusae (bai hua she she cao) * Tuber Asparagi Cochinchinensis (tian dong) * Fructus Ligustri Lucidi (nu zhen zi) * Sclerotium Poriae Cocos (fu ling) * Sclerotium Polypori Umbellati (zhu ling) * Rhizoma Atractylodis Macrocephalae (bai zhu)
* Herba Agrimoniae Pilosae (xian he cao) * Tuber Curcumae (yu jin) * Rhizoma Dioscoreae Bulbiferae (huang yao zi) * Radix Astragali Membranacei (huang qi) * Radix Pseudostellariae (tai zi shen) * Flos Lonicerae Japonicae (jin yin hua) * Radix Glycyrrhizae Uralensis (gan cao) 212
RTF2
Radiotherapy * Astragalus membranaceous (huang qi) * Panax ginseng (ren shen, ginseng) * Angelica sinensis (dang gui) * Atractylodes macrocephala (bai zhu) * Bupleurum chinense (chai hu) * Cimicifuga foetida (sheng ma) * Glycyrrhiza uralensis (gan cao) * Citrus reticulata (chen pi)
* istration before irradiation protected the jejunal crypts (p < 0.0001), increased the formation of the endogenous spleen colony (p < 0.05) and reduced the frequency of radiation-‐ induced apoptosis (Kim et al., 2002)
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Radiotherapy Compounds * L-‐glutamine * Curcumin * Probiotics * Alpha-‐lipoic acid * Resveratrol * SOD (LIFE) * Coenzyme Q10
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* Digestive enzymes * Jin Yin Hua * Melatonin * Silibinin * DIM/I3C * EGCG * Vitamin A / Retinol
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Panaxea POR
Post Operative Recovery * Radix Astragali Membranacei * Sclerotium Poriae Cocos (fu ling) (huang q)i * Pericarpium Citri Reticulatae (chen * Radix Pseudostellariae (tai zi pi) shen) * Radix Angelicae Sinensis (dang * Fructus Crataegi processed (jiao shan zha) gui) * Rhizoma Polygonati (huang jing) * Massa Medica Fermentata processed (jiao shen qu) * Caulis Millettiae Reticulatae (ji * Fructus Hordei Vulgaris Germinatus xue teng) processed (jiao mai ya) * Radix Paeoniae Rubrae (chi shao) * Fructus Lycii (gou qi zi) * Radix Rehmanniae Glutinosae * Radix Salviae Miltiorrhizae (dan (sheng di) shen) * Rhizoma Atractylodis * Fructus Ligustri Lucidi (nu zhen zi) Macrocephalae (bai zhu) * 215 Herba Epimedii (yin yang huo)
Panaxea IM1 (Immune Function) * Hericium erinaceus fruiting body * Maintains a correct balance extract 14:1 (hou tou) between cellular and * Maitake D fraction extract humoural immunity * Reishi -‐ Ganoderma lucidum (broken spore extract) * Astragalus membranaceus (huang qi) * Lentinula edodes/Shiitake extract (xiang gu) * Phellinus robiniae * Polyporus umbellatus (zhu ling) extract * Trametes versicolor (yun zhi) (extract) 216
Panaxea IM3 (Immune Function) * Cordyceps sinensis (contains extract purified polysaccharide) * Ganoderma lucidum (contains extract Ganopoly [30%]
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* Cellular immunity, cytotoxic, apoptotic, activates cellular and humoural immune response
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Panaxea AV/AT * Andrographolide treatment inhibited the proliferation of different tumour cell lines. The compound exerts direct anticancer activity on cancer cells by cell-‐cycle arrest at G0/G1 phase through induction of cell-‐cycle inhibitory protein p27 and decreased expression of cyclin-‐dependent kinase 4 (CDK4) (Rajagopal et al., 2003). * Immunostimulatory activity of andrographolide is evidenced by increased proliferation of lymphocytes and production of interleukin-‐2. Andrographolide also enhanced the TNF-‐α production and cluster of differentiation (CD) expression, resulting in increased cytotoxic activity of lymphocytes against cancer cells (Kumar et al., 2004). [email protected]
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Panaxea AV/AT * The polysaccharide fraction from Taraxii Herba, Taraxasterol showed potent immuno-‐potentiating activities with anti-‐ tumour activities. The fraction having small amount of protein inhibited the growth of solid tumour and increased peritoneal exudate cells and immuno-‐organ weights (Jeong et al., 2009). * Chlorogenic acid is a phenolic natural product isolated Flos Lonicera, is an antioxidant, an inhibitor of the tumour promoting activity of phorbol esters (Huang et al., 1988) and its active principles possess wide pharmacological actions, such as anti-‐inflammatory, antibacterial, antiviral, and antioxidative activities (Shang et al., 2011). [email protected]
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Panaxea AV/AT * Andrographolide from Andographis paniculata (chuan xin lian) * Taraxasterol from Taraxacum mongolicum (pu gong yin) * Chlorogenic Acid from Flos Lonicera (jin yin hua)
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* 3 isolates from commonly used Chinese herbs
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Tamoxifen * Tamoxifen induces cellular oxidative stress. Most breast cancer, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumour growth by tamoxifen, is unclear. * Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signalling pathways leading to the activation of activating protein-‐1 (AP-‐1), which in turn cause not only tamoxifen resistant breast cancer to develop, but lead to tamoxifen activated breast cancer.
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Panaxea BRC5
Tamoxifen Regulating Formula * Mori Albae Fructus (sang shen) * Cortex Moutan Radicis (mu dan pi) * Plastrum Testudinis (gui ban) * Fructus Ligustri Lucidi (nu Zhen Zi * Herba Ecliptae Prostratae (han lian cao) [email protected]
* Rhizoma Anemarrhenae Asphodeloidis (zhi mu) * Fructus Rosae Laevigatae (jin ying z)i * Calyx Diospyros Kaki (zhi di) * Radix Polygoni Multiflori (he shou wu) * Radix Panacis Quinquefolii (xi yang shen)
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Jia Wei Xiao Yao San * JWXYS is the most common Chinese medicine decoction co-‐ prescribed with tamoxifen (TAM) when breast cancer is treated by hormonal therapy. Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and TAM (Chen et al., 2014). * Among female breast cancer patients who had undergone TAM therapy, Chinese herbal products (CHP) consumption decreased the risk of subsequent endometrial cancer. Jia-‐ Wei-‐Xiao-‐Yao-‐San (Augmented Rambling Powder) and Shu-‐ Shu-‐Jing-‐Huo-‐Xue-‐Tang (Channel-‐Coursing Blood-‐Quickening Decoction) were the two most commonly used CHPs (Tsai et al., 2014). [email protected]
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Jia Wei Xiao Yao San * JWXYS is often co-‐prescribed with tamoxifen when breast cancer is treated by hormonal therapy (Lai et al., 2012). It is of note that some of the herbs in JWXYS are able to upregulate ERBB2 and ESR1 gene expression, while JWXYS alone does not induce any significant change in the expression of the above-‐mentioned genes. * Chui et al., (2014) attribute this to the fact that there are drug-‐ drug and drug-‐cell interactions between these components in JWXYS's composition. * Based on in vitro studies and in vivo functional studies, there is no obvious interaction between JWXYS and Tam (Chen, et al., 2014). [email protected]
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Jia Wei Xiao Yao San * Radix Bupleuri (Chai Hu) * Radix Angelicae Sinensis (Dang Gui) * Radix Paeoniae Lactiflorae (Bai Shao) * Rhizoma Atractylodis Macrocephalae processed (Chao Bai Zhu) * Sclerotium Poriae Cocos (Fu Ling) * Radix Glycyrrhizae Uralensis (Zhi Gan Cao) * Rhizoma Zingiberis Officinalis Recens (Sheng Jiang) * Cortex Moutan Radicis (Mu Dan Pi) * Fructus Gardeniae Jasminoidis (Zhi Zi) * Herba Menthae Haplocalycis (Bo He) [email protected]
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Shu Gan Liang Xue (SEEMs) * Shu-‐Gan-‐Liang-‐Xue (SGLX) a classic formula was tested on endocrine therapy-‐ associated hot flashes symptom in breast cancer patients. * For hot flashes symptom, in Chinese herbs decoction istration group, 21.9% reported symptom disappeared, 68.7% reported symptom alleviated, 9.4% reported symptom not changed; in endocrine therapy alone group, 17.9% reported symptom disappeared, 46.4% reported symptom alleviated, 35.7% reported symptom not changed (Xue, Sun, Li, 2011). * SGLX decoction, having synergistic effect on TAM, can reduce serum hormone level and alleviate the endometrial hypertrophy side effect of TAM. The results suggest that SGLXD is a potential dual aromatase-‐ sulfatase inhibitor by simultaneously down-‐regulating the expressions of CYP19 and STS in MCF-‐7 and T47D cells (Fu & Li, 2011).
Shu Gan Liang Xue * SGLX showed dose-‐dependent inhibitory effect on the proliferation of ZR-‐75-‐1 cells with IC50 value of 3.40 mg/mL. It also suppressed the stimulating effect on cell proliferation of testosterone and oestrogen sulfates (E1S). Oral istration of 6 g/kg of SGLX for 25 days resulted in a reduction in tumour volume in non-‐ovariectomized and ovariectomised nude mice. * Results suggested that SGLX showed anti-‐tumour effect on breast cancer cells both in vitro and in vivo. The anti-‐tumour activity of SGLXD is related to inhibition of aromatase and STS gene via decreasing their expression. SGLX may be considered as a novel treatment for ER positive breast cancer (Zhou et al., 2014).
Shu Gan Liang Xue * Shu-‐Gan-‐Liang-‐Xue Decoction (SGLX), a Chinese herbal formula, acts as a selective oestrogen enzyme modulators (SEEMs) agent by down-‐regulating the expression of Steroid sulfatase (STS) in the levels of transcript and enzymatic activity. * In view of the aforementioned characteristics, SGLX could serve as a novel therapeutic treatment to combat hormone-‐ dependent breast cancer (HDBC) (Zhang & Li, 2010). * SEEMs: clomifene, femarelle, ormeloxifene, raloxifene, tamoxifen, toremifene, lasofoxifene, ospemifene
Panaxea SEEMs (SGLX) * Radix Lithospermi (zi cao gen) * Cortex Moutan Radicis (mu dan pi) * Fructus Schisandrae Chinensis (wu wei zi) * Radix Paeoniae Alba (bai shao) * Radix Bupleuri Chinensis (chai hu) * Radix Curcumae Wenyu-‐jin (yu jin) * Radix Cynanchi Atrati (bai wei)
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Tamoxifen Paper * Drug Herb Interactions: Tamoxifen * http://www.elotus.org/content/drug-‐herb-‐interactions-‐ tamoxifen-‐mm-‐van-‐benschoten-‐omd * M.M. Van Benschoten: [email protected]
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Multi-‐Drug Resistance * MDR is defined as insensitivity of cancer cells to cytotoxic and cytostatic actions of a number of structurally and functionally unrelated drugs. Cancer cells are intrinsically resistant to anti-‐ cancer agents because of genetic and epigenetic heterogeneity. * Also, there are some host factors which include poor absorption, rapid metabolism and excretion that can result in low serum drug levels. The mechanisms include alteration in the expression of proteins involved in the apoptotic signalling such as p53, Bcl2 family of proteins
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Multi-‐Drug Resistance * Multidrug-‐resistance (MDR) is the chief limitation to the success of chemotherapy. According to the National Cancer Institute, multidrug-‐resistance is a phenomenon where cancer cells adopt to anti-‐tumour drugs in such a way that makes the drugs less effective. Studies have shown that 40% of all human cancers develop MDR. * Deaths due to cancer occur in most of the cases when the tumour metastasises. Chemotherapy is the only choice of treatment in metastatic cancer, and MDR limits that option. * Chemotherapy kills drug-‐sensitive cells, but leaves behind a higher proportion of drug-‐resistant cells. As the tumour begins to grow again, chemotherapy may fail because the remaining 232 16/12/14 tumour cells are now resistant.
Multi-‐Drug Resistance * Ginsenosides * Rg3 reversed multi-‐drug resistance and restored the sensitivity of resistant KBV20 cell line to various anticancer drugs. Increased animal life span in an in vivo MDR model in a dose-‐independent manner (Kim SH et al, 2003; Yue et al, 2006). * Combination of purified saponins containing Rb1, Rb2, Rc, Rd, Re and Rg1 reversed MDR (Liu et al, 2008; Si & Tien, 2005) — Quercetin/Kaempferol
* Quercetin is less potent than kaempferol but more effective than genistein and daidzein in reversing MDR (Kioka et al, 1992). * Quercetin reverses MDR through action on mitochondrial membrane potential and the induction of apoptosis (Kothan et al, 2004)
* Puerarin * Down-‐regulates MDR1 expression via nuclear factor κ-‐B and CRE (cAMP response element) transcriptional activity (Hien et al, 2010) 233
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Multi-‐Drug Resistance * Curcumin * Enhances sensitivity to vincristine by the inhibition of P-‐gp in SGC7901/VCR cell line (Chang et al, 2006). * Curcumin derivatives reversed MDR by inhibiting P-‐gp efflux (Tang et al, 2005) * Curcumin derivatives reversed MDR by inhibiting P-‐gp efflux (Limtrakul et al, 2004).
* Honokiol * Down-‐regulates expression of P-‐glycoprotein at mRNA and protein levels in MCF-‐7/ADR, a human breast MDR cancer cell line (Xu et al, 2006)
* Quercetin * Inhibits overexpression of P-‐gp mediated by arsenite (Kioka et al, 234 16/12/14 1992).
Blood Stasis & qi Stagnation
Pain
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Herbal Hot Compress Treatment * Chuan Wu (Radix Aconiti) 100g * Advanced breast cancer pain poultice * Xi Xin (Herba Asari) 50g * Qing Pi (fructus citri reticulatae * All herbs are ground into powder, mixed with vinegar immaturus) 50g to make a paste, applied * Chuan Xiong (Rhizoma Ligustici directed on the lesion, and Chuanxiong) 50g then fixed with plastic * Ma Huang (Herba Ephedrae) 50g material. * Bing Pian (Borneolum * Apply hot compresses for Syntheticum) 50g 10–30 min to alleviate the * Zhang Nao (camphor) 50g pain * Gan Cao (Radix Glycyrrhizae) 50g 236
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Panaxea Free Movement * Gentiana macrophylla (qin jiao) * Salvia miltorrhiza (dan shen) * Panax notoginseng (san qi) * Storax Styrax (su he xiang) * Ligusticum Chuanxiong (chuan xiong) * Prunus persica (tao ren) * Carthamus tinctorius (hong hua) * Myrrha (mo yao)
* Notopterygium incisum (qiang huo) * Angelica sinensis (dang gui) * Citrus aurantium (zhi ke) * Tribulus terrestris (bai ji li) * Cyperus rotundus (xiang fu) * Stephania tetrandra (fen fang ji) * Achyranthes bidentata (chuan niu xi) * Manganese 237
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Jing Huo Xue Tang * Radix Ledebouriellae (fang feng) * Radix Notopterygium (qiang huo) * Radix Angelica Dahuricae (bai zhi) * Radix Rehmanniae (sheng di) * Radix Gentianae (long dan cao) * Poriae Cocos (fu ling) * Radix Clematidis (wei ling xian) * Rhizoma Atractylodes lancea (cang zhu)
* Pericarpium Citri Reticulatae (chen pi) * Rhizoma Ligustici Chuanxiong * Semen Persicae (tao ren) * Radix Cyathulae (chuan niu xi) * Radix Angelicae Sinensis (dang gui) * Radix Paeoniae Alba (bai shao) * Radix Stephaniae Tetandrae (han fang ji) * Radix Glycyrrhizae (gan cao) 238
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Zao Jiao Ci Ju Pi Mi Yin * Zao Jiao Ci (Spina Gleditsiae) * These formulation are to 30g invigorate the Blood, dissipate Blood Stasis, * Qing Pi (Pericarpium Citri promote movement of qi and Reticulatae Viride) 20g alleviate pain. * Chen Pi (Pericarpium Citri * They are beneficial for breast Reticulatae) 20g cancer patients with varying * Wang Bu Liu Xing Zi (Semen symptoms of Stagnant qi, Vaccariae 20g Stasis of Blood, and pain. * Yu Jin (Radix Curcumae) 15g * honey 30g [email protected]
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Cautions & Contraindications
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Cautions & Contraindications * Thirteen single herbal extracts and five compound recipes were found to increase either ERBB2 or ESR1 luciferase activity. * Si Wu Tang, Guan Xin Yin, and Suan Zao Ren Tang were found to increase either HER2 or ERα protein expression. In addition, Ligusticum chuanxiong was shown to have a great effect on ERBB2 gene expression and synergistically with oestrogen to stimulate MCF-‐7 cell growth. * Si Wu Tang reverses the antiproliferative effects induced by tamoxifen, including tumour weight, tumour volume, increased ERα expression, and N-‐cadherin expression (Chui et al., 2014) [email protected]
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Cautions & Contraindications * Silymarin is a mixture of polyphenolic flavonoids isolated from milk thistle (Silybum marianum) with anticancer activities reported for several organ sites. * The results showed that dietary silymarin increased the plasma concentration of free and total silibinin, a major component of silymarin, in a dose-‐dependent manner in the rat, but did not decrease either mammary tumour (MT) incidence or number. Instead silymarin modestly increased the number of 1-‐methyl-‐1-‐nitrosourea (MNU)-‐induced MTs in rats (Malewicz et al., 2006).
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This is only an introduction to the complex and artful application of Chinese herbal medicine to breast cancer
Thank You
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References * * * * * * * * * * * * * * * *
Abeer E Abd El-‐Wahab, Doaa A Ghareeb, et al. In vitro biological assessment of berberis vulgaris and its active constituent, berberine: antioxidants, anti-‐acetylcholinesterase, anti-‐diabetic and anticancer effects. BMC Complementary and Alternative Medicine 2013, 13:218 doi:10.1186/1472-‐6882-‐13-‐218 Abedin M, King N. Diverse evolutionary paths to cell adhesion. Trends in Cell Biology 2010 20 (12): 734–742. doi:10.1016/j.tcb. 2010.08.002. Akashi T, Saito N, Hirota H, Ayabe S. Anthocyanin-‐producing dandelion callus as a chalcone synthase source in recombinant polyketide reductase assay. Phytochemistry. 1997 Sep;46(2):283-‐7. Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). The FASEB Journal. 1990 vol. 4 no. 11 2860-‐2867 Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 2008, 25:2097-‐2116. Axelson M, Kirk DN, Farrant RD, Cooley G, Lawson AM, Setchell KDR. The identification of the weak oestrogen equol [7-‐hydroxy-‐3-‐ (4′-‐hydroxyphenyl)chroman] in human urine. Biochem J. 1982;201:353–7. Azarnia R, Larsen WJ. Intercellular Communication and Cancer. Intercellular Communication 1977, pp 145-‐172 Bachg D, Haselhorst U. Effect of combined treatment with Haelan 951 in breast cancer cell line BT474. Townsend Lett 2007;5:73–84. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001, 357:539-‐545. Bang S-‐C, Kim Y, Lee J-‐H & Ahn B-‐Z. Triterpenoid Saponins from the Roots of Pulsatilla koreana. Journal of Natural Products. 2005, 68 (2), Pp. 268–72. DOI: 10.1021/np049813h Baronzio G, Schwartz L, Crespi E. Early clinical and toxicological results of a combination of natural glycolysis inhibitors on cancer patients. Biomedical Research 2012; 23: SI 219-‐223 Behrens J. The role of cell adhesion molecules in cancer invasion and metastasis. Breast Cancer Res Treat. 1993;24(3):175-‐84. Benoy I, Salgado R, Colpaert C, et al. Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. Clin Breast Cancer. 2002 Jan;2(4):311-‐5. Bilal I, Chowdhury A, Davidson J, Whitehead S. Phytoestrogens and prevention of breast cancer: The contentious debate. World J Clin Oncol 2014; 5(4): 705-‐712 Available from: URL: http:// www.wjgnet.com/2218-‐4333/full/v5/i4/705.htm DOI: http:// dx.doi.org/ 10.5306/wjco.v5.i4.705 Biochemical Pharmacology. Volume 60, Issue 2, 15 July 2000, P244 ages 167-‐177. doi:10.1016/S0006-‐2952(00)00307-‐5 16/12/14 Biochemical Pharmacology. Volume 63, Issue 6, 15 March 2002, Pp 1085-‐97. doi:10.1016/S0006-‐2952(02)00856-‐0
References * * * * * * * * * * * * * *
Blanco D, Vicent, S, Fraga, MF, Fernandez-‐Garcia I, et al. Molecular analysis of a multistep lung cancer model induced by chronic inflammation. 2007 Neoplasia, 9(10),PP. 840–52. Bobek V, Boubelik M, Fiserova A, et al. Anticoagulant drugs increase natural killer cell activity in lung cancer. Lung Cancer. 2005 47, 215–223. Byrne C, Divekar SD, Storchan GB, et al. Metals and breast cancer. J Mammary Gland Biol Neoplasia. 2013 Mar;18(1):63-‐73. doi: 10.1007/ s10911-‐013-‐9273-‐9. Campbell NE, Kellenberger L, Greenaway J, et al. Extracellular Matrix Proteins and Tumor Angiogenesis. Journal of Oncology. Volume 2010 (2010) http://dx.doi.org/10.1155/2010/586905 Cauley JA, Zmuda JM, Danielson ME, et al. Estrogen metabolites and the risk of breast cancer in older women. Epidemiology. 2003 Nov;14(6):740-‐4. Cavallini DC, Suzuki JY, Abdalla DS, et al. Influence of a probiotic soy product on faecal microbiota and its association with cardiovascular risk factors in an animal model. Lipids Health Dis. 2011 Jul 29;10:126. doi: 10.1186/1476-‐511X-‐10-‐126. Chambers RC, Laurent GJ. Coagulation cascade proteases and tissue fibrosis. Biochemical Society Transactions 2002, 30(2) Pp.194-‐200 DOI: 10.1042/0300-‐5127:0300194 Chan K. (1995). Progress in traditional Chinese medicine. Trends in Pharmacological Sciences, 16(6),Pp. 182–7. doi: 10.1016/S0165-‐6147(00)89019-‐7 Chang WH, Liu JJ, Chen CH, Huang TS, and Lu FJ: Growth inhibition and induction of apoptosis in MCF-‐7 breast cancer cells by fermented soy milk. Nutr Cancer 43, 214–226, 2002. Chen GG, Lai PBS, Hu X et al. Negative correlation between the ratio of Bax to Bcl-‐2 and the size of tumor treated by culture supernatants from Kupffer cells. Clinical & Experimental Metastasis 09-‐2002, Volume 19, Issue 5, pp 457-‐464 Chen Z, K. Gu, Y. Zheng, W. Zheng, W. Lu, and X. O. Shu. The use of complementary and alternative medicine among Chinese women with breast cancer. Journal of Alternative and Complementary Medicine, vol. 14, no. 8, pp. 1049–1055, 2008. Chen JP, Chiu SW, Chok HP, Wang Z, Zheng X, Lin Y: Prevention strategies for recurrence and metastasis of breast cancer by Chinese medicine. Global Traditional Chinese Medicine 2011, 4:125-‐128. Chen JL, Chang CJ, Wang JY, et al. In vitro and in vivo effects of Jia-‐Wei-‐Xiao-‐Yao-‐San in human breast cancer MCF-‐7 cells treated with tamoxifen. Integrative Cancer Therapies. 2014 Chi KH, Chiou TJ, Li , Chen SY, Chao Y. MS-‐20, A Chemotherapeutical Adjuvant, Reduces Chemo-‐Associated Fatigue and Appetite Loss in Cancer Patients. Nutr Cancer. 2014 Oct;66(7):1211-‐9. doi: 10.1080/01635581.2014.951731. Chiu JH, Chang CJ, Wu JC, et al. Screening to Identify Commonly Used Chinese Herbs That Affect ERBB2 and ESR1 Gene Expression 245 16/12/14 Using the Human Breast Cancer MCF-‐7 Cell Line. Evid Based Complement Alternat Med. 2014;2014:965486. doi: 10.1155/2014/965486.
References * * * * * * * * * * * * * * *
Cho RW, Wang X, Diehn M, et al. Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-‐Wnt-‐1 Murine Breast Tumors. STEM CELLS. Volume 26, Issue 2, pages 364–371, February 2008 Chung H, Jung Y-‐M, Shin D-‐H, et al. Anticancer effects of wogonin in both estrogen receptor-‐positive and -‐negative human breast cancer cell lines in vitro and in nude mice xenografts. International Journal of Cancer. 2008;122(4):816–822. Cohen I, Tagliaferri M, Tripathy D. Traditional Chinese medicine in the treatment of breast cancer. Semin Oncol. 2002 Dec;29(6): 563-‐74. Collins LC, Tamimi RM, Baer HJ, Connoly JL, Colditz GA, Schnitt SJ. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy. Results from the Nurses' Health Study. Cancer. 2005;103:1778–1784. doi: 10.1002/cncr.20979 Collins NH, et al. Characterization of Antiestrogenic Activity of the Chinese Herb, Prunella vulgaris, Using In Vitro and In Vivo (Mouse Xenograft) Models. Biol Reprod. Feb 2009; 80(2): 375–383. doi: 10.1095/biolreprod.107.065375. Cui Y, Shu X-‐O, Gao Yt, et al. Use of complementary and alternative medicine by Chinese women with breast cancer. Breast Cancer Research and Treatment. June 2004, Volume 85, Issue 3, pp 263-‐270 Cultural China (accessed 30 Aug 2014) http://history.cultural-‐china.com/en/50History3525.html Dai Z, Wan X, Kang H, et al. Clinical effects of shenqi fuzheng injection in the neoadjuvant chemotherapy for local advanced breast cancer and the effects on T-‐lymphocyte subsets. J Tradit Chin Med. 2008 Mar;28(1):34-‐8. Dalessandri KM, Firestone GL, Fitch MD, et al. Pilot study: effect of 3,3'-‐diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-‐stage breast cancer. Nutr Cancer. 2004;50(2):161-‐7. Dalgleish AG and O’Byrne K. Inflammation and Cancer: The Role of the Immune Response and Angiogenesis Pp.1-‐38 In The Link Between Inflammation and Cancer. Dalgleish AG and O’Byrne K Eds. Springer 2006. 10.1007/b137303 Darbre PD. Aluminium, antiperspirants and breast cancer. J Inorg Biochem. 2005 Sep;99(9):1912-‐9. De Angel RE, Smith SM, Glickman RD, Perkins SN, Hursting SD. Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancer. Nutr Cancer. 2010;62(8):1074-‐86. doi: 10.1080/01635581.2010.492092. DeClerck YA, Imren S. Protease inhibitors: Role and potential therapeutic use in human cancer. European Journal of Cancer. Volume 30, Issue 14, 1994, Pp 2170–80 DOI: 10.1016/0959-‐8049(94)00460-‐M Dehen R. Regression of ductal carcinoma in situ after treatment with acupuncture. J Altern Complement Med. 2013 Nov;19(11): 911-‐5. doi: 10.1089/acm.2012.0696. Del Poeta G et al. The amount of spontaneous apoptosis detected by bax/bcl-‐2 ratio predicts outcome in acute myeloid leukemia 246 16/12/14 (AML). Blood. 2002 doi:10.1182/blood-‐2002-‐06-‐1714
References *
* * * * * * *
* * * *
Fan G-‐W, Gao X-‐M, Wang H, et al. The anti-‐inflammatory activities of Tanshinone IIA, an active component of TCM, are mediated by estrogen receptor activation and inhibition of iNOS. The Journal of Steroid Biochemistry and Molecular Biology. Volume 113, Issues 3–5, February 2009, Pages 275–280 Franek KJ, Zhou Zt, Zhang W-‐D & Chen WY. In vitro studies of baicalin alone or in combination with Salvia miltiorrhiza extract as a potential anti-‐cancer agent. International journal of oncology. 2005, vol. 26, no1, Pp. 217-‐24. Fu X-‐s & Li P-‐p. Shu-‐Gan-‐Liang-‐Xue Decoction Simultaneously Down-‐regulates Expressions of Aromatase and Steroid Sulfatase in Estrogen Receptor Positive Breast Cancer Cells. Chin J Cancer Research. Sept 2011; 23(3):208-‐13 Fujita T, Takeda Y, Sun HD, et al. Cytotoxic and antitumor activities of Rabdosia diterpenoids. Planta Med 1988; 54:414–417. Gao J-‐L, Shi J-‐M, He K, et al. Yanhusuo extract inhibits metastasis of breast cancer cells by modulating mitogen-‐activated protein kinase signaling pathways. Oncology reports. 2008, vol. 20, no4, pp. 819-‐824 Gao JL, Shi JM, He K, et al. Yanhusuo extract inhibits metastasis of breast cancer cells by modulating mitogen-‐activated protein kinase signaling pathways. Oncol Rep. 2008 Oct;20(4):819-‐24. Gao JL, He TC, Li YB, Wang YT. A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-‐tumor activity. Oncology Reports. 22:1077-‐83, 2009 Gao J, W. A. Morgan, A. Sanchez-‐Medina, and O. Corcoran, The ethanol extract of Scutellaria baicalensis and the active compounds induce cell cycle arrest and apoptosis including upregulation of p53 and Bax in human lung cancer cells. Toxicology and Applied Pharmacology, vol. 254, no. 3, pp. 221–228, 2011. Garg AK, Buchholz TA, & Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal, 2005 7(11-‐12), 1630-‐164 Gay LJ & Felding-‐Habermann B. Contribution of platelets to tumour metastasis. Nature Reviews Cancer. 2011 11, 123–134. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nature Reviews Cancer 14,430– 439 (2014) doi:10.1038/nrc3726 Gu G, Barone I, Gelsomino L, et al. Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERα/Sp1-‐mediated p53 activation. J Cell Physiol. 2012 Oct;227(10):3363-‐72. doi: 10.1002/j.24035. 247
16/12/14
References *
*
* * * * * *
*
Hämäläinen M, Nieminen R, Vuorela P, et al. Anti-‐Inflammatory Effects of Flavonoids: Genistein, Kaempferol, Quercetin, and Daidzein Inhibit STAT-‐1 and NF-‐κB Activations, Whereas Flavone, Isorhamnetin, Naringenin, and Pelargonidin Inhibit only NF-‐κB Activation along with Their Inhibitory Effect on iNOS Expression and NO Production in Activated Macrophages. Mediators of Inflammation. Volume 2007 http://dx.doi.org/10.1155/2007/45673 He Yh, Zheng X, Sit C, et al. Using association rules mining to explore pattern of Chinese medicinal formulae (prescription) in treating and preventing breast cancer recurrence and metastasis. Journal of Translational Medicine 2012, 10(Suppl 1):S12 doi: 10.1186/1479-‐5876-‐10-‐S1-‐S12 Henan Medical Institute, Henan Medical College, Yunnan Institute of Botany. Oridonin-‐-‐a new antitumor subject. Chin Science Bull 1978; 23:53–56. Holtkamp W, Nagel GA, Wander H-‐E, et al. Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. International Journal of Cancer. Volume 34, Issue 3, pages 323–328, 1 September 1984. DOI: 10.1002/ijc.2910340307 Hortobagyi GN, de la Garza Salazar J, Pritchard K, et al. ABREAST Investigators: The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 2005, 6:391-‐401. Hsiao WL, Liu L. The role of traditional Chinese herbal medicines in cancer therapy-‐-‐from TCM theory to mechanistic insights. Planta Med. 2010 Aug;76(11):1118-‐31. doi: 10.1055/s-‐0030-‐1250186. Hsu YL, Yen MH, Kuo PL, et al. San-‐Zhong-‐Kui-‐Jian-‐Tang, a traditional Chinese medicine prescription, inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis. Biol Pharm Bull. 2006; 29 2388-‐2394 Hu Yy, Chen X, Duan Hq, Hu Yl & Mu X. Pulsatilla decoction and its active ingredients inhibit secretion of NO, ET-‐1, TNF-‐, and IL-‐1 in LPS-‐induced rat intestinal microvascular endothelial cells. 2010 Cell Biochemistry and Function Cell Biochemistry and Function. Vol. 27 Issue 5, Pp. 284-‐8. DOI:10.1002/cbf.1570 Hu M, Lv GM, Chen RZ, et al. Treatment of Advanced Breast Cancer with Chinese Medicinal Herbs of Fei Decoction: A Case Report. Curr Pharm Biotechnol. 2014 Apr 8.
248
16/12/14
References * * * * * * * * * * * * *
Huang ZF, Wei JS, Li HZ, Tan ZO, Zhang ZJ, Chen C. Effect of Shenqi Fuzheng injection combined with chemotherapy on thirty patients with advanced breast cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008; 28 152-‐154 Huang MT, Smart RC, Wong C, et al. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse skin by 12-‐O-‐tetradecanoylphorbol-‐13-‐acetate. Cancer Research Journal, 1988;48: 5941-‐5946 Huang Z, Chen G, Shi P. Emodin-‐induced apoptosis in human breast cancer BCap-‐37 cells through the mitochondrial signaling pathway. Archives of Pharmacal Research June 2008, Volume 31, Issue 6, pp 742-‐748 Huang PH, Huang CY, Chen MC, et al. Emodin and Aloe-‐Emodin Suppress Breast Cancer Cell Proliferation through ER α Inhibition. Evid Based Complement Alternat Med. 2013;2013:376123. doi: 10.1155/2013/376123. Hwang JT, Park OJ, Lee YK, et al. Anti-‐tumor effect of luteolin is accompanied by AMP-‐activated protein kinase and nuclear factor-‐κB modulation in HepG2 hepatocarcinoma cells. International Journal of Molecular Medicine, Volume 28, Number 1, 2011, pp. 25-‐31(7) Im JH, Fu W, Wang H, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Research, 2004 64, 8613–8619 International Menopause Society.org http://www.imsociety.org/updates_view_open.php menopauseliveID=611&SESSID=jfovnf6ukbltcqŠ63iujd5 Jeong JY, Chung YB, Lee CC, Park SW, Lee CK. Studies on immunopotentiating activities of antitumour polysaccharide from aerial parts of Taraxacum platycarpum. Biological & Pharmaceutical Journal. 2009;22(6): 602-‐5 Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-‐kappaB signaling. Nutr Cancer. 2004;49(2):209-‐16. Jiang J, Slivova V, Sliva D. Ganoderma lucidum inhibits proliferation of human breast cancer cells by down-‐regulation of estrogen receptor and NF-‐κB signaling. International Journal of Oncology. 2006;29(3):695–703. Jiang WG, Ye L, Ji K, Frewer N, Ji J, Mason MD. Inhibitory effects of Yangzheng Xiaoji on angiogenesis and the role of the focal adhesion kinase pathway. Int J Oncol. 2012 Nov;41(5):1635-‐42. doi: 10.3892/ijo.2012.1627. Jiang et al. The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells. Journal of Experimental & Clinical Cancer Research 2012, 31:42 Jin D-‐Z, Yin L-‐L, Jia X-‐Q & Zhu X-‐Z. Cryptotanshinone inhibits cyclooxygenase-‐ 2 enzyme activity but not its expression. European 249 16/12/14 Journal of Pharmacology. Volume 549, Issues 1-‐3, 7 November 2006, Pp. 166-‐72. doi:10.1016/j.ejphar.2006.07.055
References * * * * * * * * * * *
*
Kang JX, Liu J, Wang J, He C, Li FP. (2005). The extract of huanglian, a medicinal herb, induces cell growth arrest and apoptosis by up-‐regulation of interferon-‐β and TNF-‐α in human breast cancer cells. Carcinogenesis, 26(11):1934-‐1939. doi:10.1093/carcin/bgi154 Kassi E, Sourlingas TG, Spiliotaki M, et al. Ursolic acid triggers apoptosis and Bcl-‐2 downregulation in MCF-‐7 breast cancer cells. Cancer Investigation, 27 (2009), pp. 723–733 Kim SH, Lee SE, Oh H, et al. Am J Chin Med. 2002;30(1):127-‐37. Kim JB, Lee K-‐M, Ko E, et al. Berberine Inhibits Growth of the Breast Cancer Cell Lines MCF-‐7 and MDA-‐MB-‐231. Planta Med 2008; 74(1): 39-‐42. DOI: 10.1055/s-‐2007-‐993779 Kim AD, K. A. Kang, R. Zhang et al. Ginseng saponin metabolite induces apoptosis in MCF-‐7 breast cancer cells through the modulation of AMP-‐activated protein kinase. Environmental Toxicology and Pharmacology, vol. 30, no. 2, pp. 134–140, 2010. Kim JB, Yu JH, Ko E, et al. (2010). The alkaloid Berberine inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell-‐cycle arrest. Phytomedicine, 17(6):436-‐40. doi: 10.1016/j.phymed.2009.08.012. Kim JB, Yu JH, Ko E, Lee KW, et al. The alkaloid Berberine inhibits the growth of Anoikis-‐resistant MCF-‐7 and MDA-‐MB-‐231 breast cancer cell lines by inducing cell cycle arrest. Phytomedicine. 2010 May;17(6):436-‐40. doi: 10.1016/j.phymed.2009.08.012. Kim KH, H.S. HS, Choi HS, et al. Induction of apoptotic cell death by ursolic acid through mitochondrial death pathway and extrinsic death receptor pathway in MDA-‐MB-‐231 cells. Archives of Pharmacal Research, 34 (2011), pp. 1363–1372 King ML, Adler SR, Murphy LL. Extraction-‐dependent effects of American ginseng (Panax quinquefolium) on human breast cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther. 2006 Sep;5(3):236-‐43 King ML, Murphy LL. American ginseng (Panax quinquefolius L.) extract alters mitogen-‐activated protein kinase cell signaling and inhibits proliferation of MCF-‐7 cells. J Exp Ther Oncol. 2007;6(2):147-‐55. Kinouchi FL, Maia DC, de Abreu Ribeiro LC, et al. A soy-‐based product fermented by Enterococcus faecium and Lactobacillus helveticus inhibits the development of murine breast adenocarcinoma. Food Chem Toxicol. 2012 Nov;50(11):4144-‐8. doi: 10.1016/ j.fct.2012.08.038. Kopp HG, Placke T & Salih HR. Platelet-‐derived transforming growth factor-‐beta down-‐regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Research 2009 69, 7775–7783. 250
16/12/14
References * * * * * * * *
*
*
Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011;121(10):3804–3809. doi:10.1172/JCI57099. Kumar RA, Sridevi K, Kumar NV, Nanduri S, Rajagopal S. Anticancer and immunostimulatory compounds from Andrographis paniculata. Journal of Ethnopharmacology. 2004 92(2-‐3): 291-‐295. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med 2000, 248:171-‐183. Labelle M, Begum S & Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-‐mesenchymal-‐like transition and promotes metastasis. Cancer Cell. 2011 20, 576–590. Lai J-‐N, Wu C-‐T, Wang J-‐D. Prescription Pattern of Chinese Herbal Products for Breast Cancer in Taiwan: A Population-‐Based Study. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/891893 Lee E, Levine EA, Franco VI, et al. Combined Genetic and Nutritional Risk Models of Triple Negative Breast Cancer. Nutrition and Cancer. 2014 66:6, 955-‐963, DOI: 10.1080/01635581.2014.932397 Leitman DC, Christians U. MF101: a multi-‐component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs. 2012 Jul;21(7):1031-‐42. doi: 10.1517/13543784.2012.685652. Li Y, Fan L, Sun Y, Miao X, et al. Paris saponin VII from trillium tschonoskii reverses multidrug resistance of adriamycin-‐resistant MCF-‐7/ADR cells via P-‐glycoprotein inhibition and apoptosis augmentation. J Ethnopharmacol. 2014 Jul 3;154(3):728-‐34. doi: 10.1016/j.jep.2014.04.049. Li JW, Liu XF, Chen HZ, Chen HH, Shi GX, Wang SJ. [Effect of yanghe huayan decoction on precancerosis of breast cancer, protein and mRNA expression of ki67: an experimental research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014 Aug;34(8):970-‐5. [Article in Chinese] Liao F. Herbs of activating blood circulation to remove blood stasis. Clinical Hemorheology and Microcirculation. Volume 23, Numbers 2-‐4/2000
251
16/12/14
References * * * * * *
* * *
*
Lai J-‐N, Wu C-‐T, Wang J-‐D. Prescription Pattern of Chinese Herbal Products for Breast Cancer in Taiwan: A Population-‐Based Study. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012) http://dx.doi.org/10.1155/2012/891893 Lecumberri E, Dupertuis YM, Miralbell R, Pichard C. Green tea polyphenol epigallocatechin-‐3-‐gallate (EGCG) as adjuvant in cancer therapy. Clinical Nutrition. Volume 32, Issue 6, December 2013, Pages 894–903 Lee SJ, K. Park, S. D. Ha, W. J. Kim, and S. K. Moon. Gleditsia sinensis thorn extract inhibits human colon cancer cells: the role of ERK1/2, G2/M-‐phase cell cycle arrest and p53 expression. Phytotherapy Research, vol. 24, no. 12, pp. 1870–1876, 2010. Leitman DC, Christians U. MF101: a multi-‐component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms. Expert Opin Investig Drugs. 2012 Jul;21(7):1031-‐42. doi: 10.1517/13543784.2012.685652. Li-‐Weber M. Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Letters. Volume 332, Issue 2 , Pages 304-‐312, 28 May 2013. doi:10.1016/j.canlet.2010.07.015 Li Y, Fan L, Sun Y, Miao X, et al. Paris saponin VII from trillium tschonoskii reverses multidrug resistance of adriamycin-‐resistant MCF-‐7/ADR cells via P-‐glycoprotein inhibition and apoptosis augmentation. J Ethnopharmacol. 2014 Jul 3;154(3):728-‐34. doi: 10.1016/j.jep.2014.04.049. Liao F. Herbs of activating blood circulation to remove blood stasis. Clinical Hemorheology and Microcirculation. Volume 23, Numbers 2-‐4/2000 Lin Y, et al. Breast Cancer Stages in TCM. [in Chinese] JCIM Journal 2006 Vol.4, No.5 DOI: 10.3736/jcim20060502 Lin Y-‐s, Tsai P-‐h, Kandaswami CC, et al. Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial– mesenchymal transition in A431 epidermal cancer cells. Cancer Science. Volume 102, Issue 10, pages 1829–1839, October 2011 DOI: 10.1111/j.1349-‐7006.2011.02035.x Lin C-‐H, Shen Y-‐A, Hung P-‐H, et al. Epigallocathechin gallate, polyphenol present in green tea, inhibits stem-‐like characteristics and epithelial-‐mesenchymal transition in nasopharyngeal cancer cell lines BMC Complementary and Alternative Medicine 2012, 12:201 doi:10.1186/1472-‐6882-‐12-‐201
16/12/14
References *
* *
* * * * * * * *
Lissoni P, Malugani F, Bonfanti A, Bucovec R, et al. Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-‐12 and endothelin-‐1. Journal of Biological Regulators and Homeostatic Agents 2001, 15(2):140-‐144 Liu H, Zang C, Emde A, et al. Anti-‐tumor effect of honokiol alone and in combination with other anti-‐cancer agents in breast cancer. Eur J Pharmacol. 2008 Sep 4;591(1-‐3):43-‐51. doi: 10.1016/j.ejphar.2008.06.026. Liu Y, Yin H-‐J, Shi D-‐z, Chen K-‐j. Chinese Herb and Formulas for Promoting Blood Circulation and Removing Blood Stasis and Antiplatelet Therapies. Evidence-‐Based Complementary and Alternative Medicine. Volume 2012 (2012), http://dx.doi.org/ 10.1155/2012/184503 Liu Y, Cao W, Zhang B, et al. The natural compound magnolol inhibits invasion and exhibits potential in human breast cancer therapy. Sci Rep. 2013 Nov 14;3:3098. doi: 10.1038/srep03098. Liu W, Xu J, Liu Y, et al. Anthocyanins potentiate the activity of trastuzumab in human epidermal growth factor receptor 2-‐positive breast cancer cells in vitro and in vivo. Mol Med Rep. 2014 Oct;10(4):1921-‐6. doi: 10.3892/mmr.2014.2414. Lu Y, Lu YX. Clinical application and pharmacology function of Shenqi fuzheng injection. Li Shi Zhen Medicine and material medica research 2006, 17(10):2083-‐2085. Liu Y-‐d, et al. The Influence of Baicalin on the level of Serum TNF-‐α, IL-‐6, IL-‐10 in Diet-‐induced Hyperlipidemic and n-‐infected Mice. Si Chuan Zhong Yi. 2006; 24(9): Pp.19-‐20. Lu Q, Zhang P, Zhang X, Chen J. Experimental study of the anti-‐cancer mechanism of tanshinone IIA against human breast cancer. Int J Mol Med. 2009 Dec;24(6):773-‐80. Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression JCB. 2012 Vol.196 no.4 395-‐406 doi: 10.1083/jcb.201102147 Malewicz B, Wang Z, Jiang C, et al. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis. 2006 Sep;27(9):1739-‐47. Marques M, Laflamme L, Benassou I, et al. Low levels of 3,3'-‐diindolylmethane activate estrogen receptor α and induce proliferation of breast cancer cells in the absence of estradiol. BMC Cancer. 2014 Jul 21;14(1):524. doi: 10.1186/1471-‐2407-‐14-‐524. 253
16/12/14
References * * * * * * * * * * * * *
*
Matsumoto H, Wada T, Fukunaga K, et al. Bax to Bcl-‐2 Ratio and Ki-‐67 Index are Useful Predictors of Neoadjuvant Chemoradiation Therapy in Bladder Cancer. Jpn. J. Clin. Oncol. (2004) 34 (3): 124-‐130. doi: 10.1093/jjco/hyh026 Matthews AK, S. A. Sellergren, D. Huo, M. List, and G. Fleming. Complementary and alternative medicine use among breast cancer survivors. Journal of Alternative and Complementary Medicine, vol. 13, no. 5, pp. 555–562, 2007. Mocellin S, Nitti D. TNF and cancer: the two sides of the coin. Front Biosci. 2008 Jan 1;13:2774-‐83. Morel A-‐P, Lièvre M, Thomas C, Hinkal G, Ansieau S, et al. Generation of Breast Cancer Stem Cells through Epithelial-‐Mesenchymal Transition. PLoS ONE. 2008 3(8): e2888. doi:10.1371/journal.pone.0002888 Mueck AO, Seeger H. Breast cancer: are estrogen metabolites carcinogenic? Climacteric 2007;10(Suppl2):62-‐5. http://www.ncbi.nlm.nih.gov/pubmed/17882675 Mukherjee AK, Basu S, Sarkar N, Ghosh AC. Advances in cancer therapy with plant based natural products. Curr Med Chem 2001, 8:1467-‐1486. NCI. http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page2 Nicastro HL, Firestone GL, Bjeldanes LF. 3,3'-‐diindolylmethane rapidly and selectively inhibits hepatocyte growth factor/c-‐Met signaling in breast cancer cells. J Nutr Biochem. 2013 Nov;24(11):1882-‐8. doi: 10.1016/j.jnutbio.2013.05.004. Oh YC, Choi JG, Lee YS, Brice OO, et al. Corydalis alkaloid Tetrahydropalmatine inhibits pro-‐inflammatory mediators in lipopolysaccharide-‐stimulated THP-‐1 cells. J Med Food. 2010 Oct;13(5):1125-‐32. Oka H, Shiozaki H, Kobayashi K, et al. Expression of E-‐cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res. 1993 Apr 1;53(7):1696-‐701. Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013 Aug;22 Suppl 2:S66-‐72. doi: 10.1016/j.breast.2013.07.012. Pal S, Bhattacharjee A, Ali A, et al. Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism. Journal of Inflammation. 2014, 11:23 doi:10.1186/1476-‐9255-‐11-‐23 http://www.journal-‐inflammation.com/content/11/1/23 Palumbo JS, Talmage KE, Massari JV, et al. (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer 16/12/14 cell-‐mediated elimination of tumor cells. Blood, 105, 178–185. 254
References * * * *
* * * * *
* * *
Palumbo JS, Talmage KE, Massari JV, et al. (2007) Tumor cell-‐associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-‐dependent and-‐independent mechanisms. Blood, 110, 133–141. Park JE, et al. Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive Human Tumor Stromal Fibroblasts. The Journal of Biological Chemistry, 274, Pp.36505-‐12. 1999 doi: 10.1074/jbc.274.51.36505 Park IJ, Kim MJ, Park OJ, et al. Cryptotanshinone induces ER stress-‐mediated apoptosis in HepG2 and MCF7 cells. Apoptosis. 2012 Mar;17(3):248-‐57. doi: 10.1007/s10495-‐011-‐0680-‐3. Patel DD, Bhatavdekar JM, Chikhlikar PR, et al. Node negative breast carcinoma: Hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. Journal of Surgical Oncology. Volume 62, Issue 2, pages 86–92, June 1996. DOI: 10.1002/(SICI)1096-‐9098(199606)62:2<86::AID-‐JSO3>3.0.CO;2-‐M Payandeh M, et al. P53 mutation compared with Ki67 marker in metastasis of breast cancer in western Iran. Journ Solid Tumors. 2014 DOI: 10.5430/jst.v4n3p4 Peppercorn J. Breast Cancer in Women Under 40. 2009 Oncology 23 (6) Perez AT, Arun B, Tripathy D, Tagliaferri MA, et al. A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer. Breast Cancer Res Treat. 2010 Feb;120(1):111-‐8. doi: 10.1007/s10549-‐009-‐0678-‐5. Perwez-‐Hussain S, & Harris CC. Inflammation and cancer: an ancient link with novel potentials. International Journal of Cancer, 2007 121(11), PP.2373–80. Peterson G, Barnes S. Genistein inhibition of the growth of human breast cancer cells: Independence from estrogen receptors and the multi-‐drug resistance gene. Biochemical and Biophysical Research Communications. Volume 179, Issue 1, 30 August 1991, Pages 661–667 Rachmut IH, Samuels N, Melnick SJ, Ramachandran C, et al. Immunomodulatory effects of the botanical compound LCS101: implications for cancer treatment. 2013 Onco Targets Ther, 6:437–445. doi: 10.2147/OTT.S42038 Rajagopal S, kumar SA, Dhanvanthri S. et al. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. Journal of Experimental Therapeutics and Oncology. Volume 3, Issue 3, pages 147–158, May 2003 Rajah TT, Du N, Drews N, Cohn R. Genistein in the presence of 17beta-‐estradiol inhibits proliferation of ERbeta breast cancer cells. Pharmacology. 2009;84(2):68-‐73. doi: 10.1159/000226123. 255 16/12/14
References * * * * * * * *
* * * *
Ren Ls & Zhang H. Studies on the Anti-‐tumour Action of Lignum Sappan. China Journal of Chinese Materia Medica. 1990;05 DOI： conk:ISSN:1001-‐5302.0.1990-‐05-‐030 Ren Z-‐H, Tong Y-‐H,Xu W, Ma J, Chen Y. Tanshinone II A attenuates inflammatory responses of rats with myocardial infarction by reducing M-‐1 expression. Phytomedicine. Volume 17, Issues 3–4, March 2010, Pages 212–218 Rogan EG and Cavalieri EL. (2011) Oxidative Stress in the Metabolism of Estrogens Leading to Cancer Initiation: Prevention by Specific Antioxidants. In Oxidative Stress: Diagnostics, Prevention, and Therapy. Chapter 4. DOI: 10.1021/bk-‐2011-‐1083.ch004 Saunders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-‐term follow-‐up. Cancer. 2005;103:2481–2484. doi: 10.1002/cncr.21069. Shang X, Pan H, Li M, Miao X, Ding H. Lonicera japonica Thunb.: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine. Journal of Ethnopharmacology. Volume 138, Issue 1, 31 October 2011, Pages 1–21 DOI: 10.1016/j.jep.2011.08.016 Shao J-‐w, Dong H-‐y, Wang T, Guo Y-‐h. Traditional Chinese medicine Rhizoma curcumae activates PXR and affects cytochrome P450 3A in the rat liver. Zhong Guo Yao Li Xue Tong Bao. 2008, 24(4): 504-‐509 Shi J, et al. Characterization of Aromatase Binding Agents from the Dichloromethane Extract of Corydalis yanhusuo Using Ultrafiltration and Liquid Chromatography Tandem Mass SpectrometryMolecules 2010, 15, 3556-‐3566; doi:10.3390/ molecules15053556 Schonthal AH. Targeting endoplasmic reticulum stress for cancer therapy. Front Biosci (Schol Ed). 2012 Jan 1;4:412-‐31.Schulz M, Hoffmann K, Weikert C, et al. Identification of a dietary pattern characterized by high-‐fat food choices associated with increased risk of breast cancer: the European Prospective Investigation into Cancer and Nutrition (EPIC)-‐Potsdam Study. Br J Nutr 2008, 100:942-‐946. Serafim TL, F. S. Carvalho, M. P. M. Marques et al. Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. Chemical Research in Toxicology, vol. 24, no. 5, pp. 763–774, 2011. Setchell KDR, Borriello SP, Hulme P, Kirk DN, Axelson M. Nonsteroidal estrogens of dietary origin: possible roles in hormone-‐ dependent disease. Am J Clin Nutr. 1984;40:569–78. Shao Sj, Wu Xq, Feng J, et al. Effect of Ru’ai Shuhou Recipe on HER2 signal transduction pathway and related matrix proteins during the process of recurrence and metastasis of HER2 over-‐expression in rats with breast cancer. Shang Hai Zhong Yi Yao Za Zhi. 2013, 47(6): 89-‐92. 16/12/14 Sotoca AM, Ratman D, van der Saag P, et al. Phytoestrogen-‐mediated inhibition of proliferation of the human T47D breast cancer cells depends on the ERalpha/ERbeta ratio. J Steroid Biochem Mol Biol. 2008 Dec;112(4-‐5):171-‐8. doi: 10.1016/j.jsbmb.2008.10.002.
References * * * * * * * * * * * * * * *
Stark A, Madar Z. (2002). Phytoestrogens: a review of recent findings. J Pediatr Endocrinol Metab, 15(5):561-‐72. Stewart CA, Vivier E & Colonna M. Strategies of natural killer cell recognition and signaling. Current Topics in Microbiology and Immunology. 2006 298, 1–21. Stovall DW, Pinkerton JV. MF-‐101, an estrogen receptor beta agonist for the treatment of vasomotor symptoms in peri-‐ and postmenopausal women. Curr Opin Investig Drugs. 2009 Apr;10(4):365-‐71. Suganuma M, Okabe S, Kurusu M, et al. Discrete roles of cytokines, TNF-‐alpha, IL-‐1, IL-‐6 in tumor promotion and cell transformation. Int J Oncol. 2002 Jan;20(1):131-‐6. Sun DZ, Xu L, Wei PK, Liu L, He J. Syndrome differentiation in traditional Chinese medicine and E-‐cadherin/ICAM-‐1 gene protein expression in gastric carcinoma. World J Gastroenterol. 2007 Aug 28;13(32):4321-‐7. Tang W, Eisenbrand G. Chinese drugs of plant origin: chemistry, pharmacology, and use in traditional and modern medicine. Berlin: Springer-‐Verlag. 1992:817–847. Tao J, Zhang P, Liu G, et al. Cytotoxicity of Chinese motherwort (YiMuCao) aqueous ethanol extract is non-‐apoptotic and estrogen receptor independent on human breast cancer cells. J Ethnopharmacol. 2009 Mar 18;122(2):234-‐9. Tsai YT, Lai JN, Wu CT. The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: A population-‐based study. J Ethnopharmacol. 2014 Sep 11;155(2):1256-‐62. doi: 10.1016/j.jep.2014.07.008. Ursin G, London S, Stanczyk FZ, et al. A pilot study of urinary estrogen metabolites (16alpha-‐OHE1 and 2-‐OHE1) in postmenopausal women with and without breast cancer. Environ Health Perspect. 1997 Apr;105 Suppl 3:601-‐5. van Dijk M, Göransson SA, Strömblad S. Cell to extracellular matrix interactions and their reciprocal nature in cancer. Experimental Cell Research. Volume 319, Issue 11, 1 July 2013, Pages 1663–1670 Virk-‐Baker MK, Nagy TR, Barnes S. (2010) Role of phytoestrogens in cancer therapy. Planta Med. 2010 Aug;76(11):1132-‐42. doi: 10.1055/ s-‐0030-‐1250074. Vitale DC. Piazza, C, Melilli B, Drago F, Salomone S. (2013) Isoflavones: estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet. 2013 Mar;38(1):15-‐25. Vivar OI, Saunier EF, Leitman DC, et al. Selective activation of estrogen receptor-‐beta target genes by 3,3'-‐diindolylmethane. Endocrinology. 2010 Vol. 151, No. 4 Pp. 1662-‐7. doi:10.1210/en.2009-‐1028 Wang SC, Zhang L, Hortobagyi GN, Hung MC. Targeting HER2: recent developments and future directions for breast cancer patients. Semin Oncol. 2001 Dec;28(6 Suppl 18):21-‐9. 257 16/12/14 Wang Sm, et al. Nan Hua Da Xue Xue Bao [Chinese language medical edition]. 2007; 35(1): 4-‐6.
References * * * * * * * * * * * * * *
Wang Z-‐Y, Wang D-‐M, Loo TY, et al. Spatholobus suberectus inhibits cancer cell growth by inducing apoptosis and arresting cell cycle at G2/M checkpoint. Journal of Ethnopharmacology. Volume 133, Issue 2, 27 January 2011, Pages 751–758 Wang J, Xiao X, Zhang Y, et al. Simultaneous modulation of COX-‐2, p300, Akt, and Apaf-‐1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res. 2012 Aug;53(1):77-‐90. doi: 10.1111/j.1600-‐079X.2012.00973.x. Wang J-‐s, Ren T-‐n, Xi T. Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-‐7 human breast cancer cells. Medical Oncology. March 2012, Volume 29, Issue 1, pp 10-‐15 Wang J, Wang Q, Li L, Li Y, et al. Phlegm-‐dampness constitution: genomics, susceptibility, adjustment and treatment with traditional Chinese medicine. Am J Chin Med. 2013;41(2):253-‐62. doi: 10.1142/S0192415X13500183. Wang X, Chen YG, Ma L, et al. Effect of Chinese medical herbs-‐Huiru Yizeng Yihao on hyperprolactinemia and hyperplasia of mammary gland in mice. Afr J Tradit Complement Altern Med. 2013 May 16;10(4):24-‐35. Wang D, Lu J, Liu Y, et al. Liquiritigenin induces tumor cell death through mitogen-‐activated protein kinase-‐ (MPAKs-‐) mediated pathway in hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:965316. doi: 10.1155/2014/965316. Way T-‐D, Kao M-‐C, Lin J-‐K, et al. Apigenin Induces Apoptosis through Proteasomal Degradation of HER2/neu in HER2/neu-‐ overexpressing Breast Cancer Cells via the Phosphatidylinositol 3-‐Kinase/Akt-‐dependent Pathway. 2004 The Journal of Biological Chemistry, 279, 4479-‐4489. doi: 10.1074/jbc.M305529200 Wicha, M. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. Journal of Clinical Investigation, Vol. 120, No. 2, February 2010; doi:10.1172/JCI39397 Wong KC, Wu L-‐T. History of Chinese Medicine. Tientsin, China: The Tientsin Press 1932 Woo JH, Li D, Wilsbach K, et al. Coix seed extract, a commonly used treatment for cancer in China, inhibits NFkappaB and protein kinase C signaling. Cancer Biol. Ther 2007; 6: 2005–2011 Xian, L. & Qian, S-‐h. Progress in the Studies of Anti-‐cancer Function of Traditional Chinese Medicines. Chinese Wild Plant Resources. 2009;04. DOI: CNKI:SUN:ZYSZ.0.2009-‐04-‐000 Xiao, F-‐y., et al. Zhong Guo Zhong Yao Za Zhi. 2005; 30(22): PP.1763-‐66. Xu Yy, Zhang Y, Zhou F, et al. Human pregnane X receptor-‐mediated transcriptional regulation of CYP3A4 by extracts of 7 traditional Chinese medicines. Zhong Guo Zhong Yao Za Zhi. 2011, 36(11): 1524-‐1527. Xue D, Sun H, Li PP. Long-‐term Chinese herbs decoction istration for management of hot flashes associated with endocrine therapy in breast cancer patients. Chin J Cancer Res. 2011 Mar;23(1):74-‐8. doi: 10.1007/s11670-‐011-‐0074-‐7. 258
16/12/14
References * * * * * * * * * * * *
Yaacob NS, Hamzah N, Nik Mohamed Kamal NN, et al. Anticancer activity of a sub-‐fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro. BMC Complement Altern Med. 2010 Aug 5;10:42. doi: 10.1186/1472-‐6882-‐10-‐42. Yaacob NS, Kamal NN, Norazmi MN. Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-‐7 and MDA-‐MB-‐231 human breast cancer cell lines. BMC Complement Altern Med. 2014 Jul 18;14(1):252. doi: 10.1186/1472-‐6882-‐14-‐252. Yan YY, Zheng LS, Zhang X, et al. Blockade of Her2/neu binding to Hsp90 by emodin azide methyl anthraquinone derivative induces proteasomal degradation of Her2/neu. Mol Pharm. 2011 Oct 3;8(5):1687-‐97. doi: 10.1021/mp2000499. Yang LR, Xu XY. Clinical application and curative effect evaluation of Shenqi fuzheng injection. Heilongjiang Journal of Traditional Chinese Medicine 2004, 4:46-‐48. Yang L, Li L, Chen Y, Parkin DM. Cancer Incidence and Mortality Estimates and Prediction for year 2000 and 2005 in China. Chinese Journal of Health Statistics 2005, 22:218-‐222. Yang Xf, Liao Mc, Yang Zm, et al. Effect of Panax notoginseng on genes expression of CYP and GST in lung tissues of rats. Zhong Guo Zhong Yao Za Zhi. 2009, (17): 2236-‐2240. Yang Y-‐F, Liao J. Exploration of Key Points in Evaluation Criteria of Chinese Medicine in the Treatment of Cancer. Chin J Integr Med 2010 Feb;16(1):3-‐5 Ye L, Ji K, Frewer N, Ji J, Jiang WG. Impact of Yangzheng Xiaoji on the adhesion and migration of human cancer cells: the role of the AKT signalling pathway. Anticancer Res. 2012 Jul;32(7):2537-‐43. Yeh C-‐T, Wu C-‐H, Yen G-‐C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-‐Jun N-‐terminal kinase, Akt and mammalian target of rapamycin signaling. Molecular Nutrition & Food Research. Volume 54, Issue 9, pages 1285–1295, September 2010 DOI: 10.1002/mnfr.200900414 Yin Y, Shi R, Shen H-‐M. Luteolin, a flavonoid with potentials for cancer prevention and therapy. Curr Cancer Drug Targets. Nov 2008; 8(7):634-‐48 Yuko Izuhara Y, Takahashi S, Nangaku M, et al.Inhibition of Plasminogen Activator Inhibitor-‐1; Its Mechanism and Effectiveness on Coagulation and Fibrosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008; 28: 672-‐677, doi: 10.1161/ATVBAHA. 107.157479 Zhang L, Chang C-‐j,Bacus SS, Hung M-‐C. Suppressed Transformation and Induced Differentiation of HER-‐2/neu-‐overexpressing Breast Cancer Cells by Emodin. Cancer Res September 1, 1995 55; 3890 259 16/12/14
References *
* * * * * * * * * * *
Zhang L, Lau Y-‐K, Xia W, Hortobagyi GN, Hung M-‐C. Tyrosine Kinase Inhibitor Emodin Suppresses Growth of HER-‐2/neu-‐ overexpressing Breast Cancer Cells in Athymic Mice and Sensitizes These Cells to the Inhibitory Effect of Paclitaxel. Clin Cancer Res February 1999 5; 343 Zhang, S-‐p., et al. Tian Jin Zhong Yi. [Chinese language medical edition] 2000; 17(2):Pp. 34-‐5. Zhang, K-‐f., et al. Zun Yi Yi Xue Yuan Xue Bao. [Chinese language medical edition] 2004; 27(2):Pp. 134-‐6. Zhang YX, Chen Y, Guo XN, et al. 11,11'-‐dideoxy-‐verticillin: a natural compound possessing growth factor receptor tyrosine kinase-‐ inhibitory effect with anti-‐tumor activity. Anticancer Drugs. 2005 Jun;16(5):515-‐24. Zhang Y, Li P-‐P. Shu-‐Gan-‐Liang-‐Xue Decoction, a Chinese herbal formula, down-‐regulates the expression of steroid sulfatase genes in human breast carcinoma MCF-‐7 cells. Journal of Ethnopharmacology 127 (2010) 620–624 Zhang J, Zhan Z, Wu J, Zhang C, et al. Relationship between EGF, TGFA, and EGFR Gene Polymorphisms and Traditional Chinese Medicine ZHENG in Gastric Cancer. Evid Based Complement Alternat Med. 2013;2013:731071. doi: 10.1155/2013/731071. Zhao C, Yin S, Dong Y, et al. Autophagy-‐dependent EIF2AK3 activation compromises ursolic acid-‐induced apoptosis through upregulation of MCL1 in MCF-‐7 human breast cancer cells. Autophagy. 2013 Feb 1;9(2):196-‐207. doi: 10.4161/auto.22805. Zhong ZH. Dictate history: A national new medicine that come from experiential prescription. Journal of China Prescription Drug 2009, 1(82):33-‐36. Zhou Z-‐T & Zhang W-‐X. Effects of two Chinese herbs on proliferation during oral carcinogenesis. 2005 Oral abstract The IADR/ AADR/CADR 83rd General Session Zhou G-‐B, Chen S-‐J, Wang Z-‐Y, Chen Z. Back to the future of oridonin: again, compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo. Cell Research (2007) 17: 274–276. doi: 10.1038/cr.2007.21 Zhou Q-‐m, Wang S, Zhang H, et al. The combination of baicalin and baicalein enhances apoptosis via the ERK/p38 MAPK pathway in human breast cancer cells. Acta Pharmacologica Sinica (2009) 30: 1648–1658; doi: 10.1038/aps.2009.166 Zhou N, Han, S-‐Y, Zhou F, Li P-‐p. Anti-‐tumor effect of Shu-‐gan-‐Liang-‐Xue decoction in breast cancer is related to the inhibition of aromatase and steroid sulfatase expression. Journal of Ethnopharmacology. Volume 154, Issue 3, 3 July 2014, Pages 687–695 260
16/12/14
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