Green Tea/epigallocatechin-3-gallate (EGCG)

Rich66 · 03-06-2010, 06:53 PM

(Telomerase/CSC, G1, Cyclins, CDK 1, PCNA, IGF-1,EGFR,VEGF/HIF-1alpha, PI3k/Akt,NFkb,Ras/Raf/MAPK,Glycolysis, Aromatase, w/Pac, w/Hercep, w/TAM, w/plat, w/capsaicin, w/piperine, w/Quercetin, potent formulations)

Int J Mol Sci. 2008 Jun;9(7):1196-206. Epub 2008 Jul 12.
Tea polyphenols and their roles in cancer prevention and chemotherapy.

PDF

Chen D, Dou QP.
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan, USA.
Many plant-derived, dietary polyphenols have been studied for their chemopreventive and chemotherapeutic properties against human cancers, including green tea polyphenols, genistein (found in soy), apigenin (celery, parsley), luteolin (broccoli), quercetin (onions), kaempferol (broccoli, grapefruits), curcumin (turmeric), etc. The more we understand their involved molecular mechanisms and cellular targets, the better we could utilize these "natural gifts" for the prevention and treatment of human cancer. Furthermore, better understanding of their structure-activity relationships will guide synthesis of analog compounds with improved bio-availability, stability, potency and specificity. This review focuses on green tea polyphenols and seeks to summarize several reported biological effects of tea polyphenols in human cancer systems, highlight the molecular targets and pathways identified, and discuss the role of tea polyphenols in the prevention and treatment of human cancer. The review also briefly describes several other dietary polyphenols and their biological effects on cancer prevention and chemotherapy.

PMID: 19325799 [PubMed - in process]

Transl Oncol. 2011 Jun;4(3):147-56. Epub 2011 Jun 1.
Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors.

Stearns ME, Wang M.

Free PMC Article

Source

Department of Pathology, Drexel University College of Medicine, Philadelphia, PA, USA.

Abstract

We have examined whether epigallocatechin-3-gallate (EGCG), and extract of green tea, in combination with taxane (i.e., paclitaxel and docetaxel), exerts a synergistic activity in blocking human prostate PC-3ML tumor cell growth in vitro and in vivo. Growth assays in vitro revealed that the IC(50) values were ∼30 ÂµM, ∼3 nM, and ∼6 nM, for EGCG, paclitaxel and docetaxel, respectively. Isobolograms generated from the data clearly indicated that EGCG in combination with paclitaxel or docetaxel had an additive effect in blocking tumor cell growth. EGCG combined with taxane also had an additive effect to increase the expression of apoptotic genes, (p53, p73, p21, and caspase 3) and the percent apoptosis observed in vitro and in tumor modeling studies in severe combined immunodeficient mice. The tumor modeling studies clearly showed that EGCG plus taxane injected intraperitoneally (i.p.) induced a significant increase in apoptosis rates (TUNEL assays) and eliminated preexisting tumors generated from PC-3ML cells implanted i.p., increasing disease-free survival rates to greater than 90%. More importantly, the combination therapy (i.p. biweekly) blocked metastases after intravenous injection of PC-3ML cells through the tail vein. In mice treated with EGCG plus taxane, the disease-free survival rates increased from 0% (in untreated mice) to more than 70% to 80% in treated mice. Taken together, these data demonstrate for the first time that EGCG in combination with taxane may provide a novel therapeutic treatment of advanced prostate cancer.

Liver Int. 2009 May;29(5):670-7. Epub 2009 Feb 17.
Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells.

Lang M, Henson R, Braconi C, Patel T.
Source

Scott and White Clinic, Texas A&M University Health Sciences Center, College of Medicine, Temple, TX, USA.

Abstract

BACKGROUND:

Green tea polyphenols are chemopreventive in several cancer models but their use as adjunctive therapeutic agents for cancer is unknown.
AIMS:

Cholangiocarcinomas respond poorly to chemotherapeutic agents and our aims were to assess the utility of green tea polyphenols as adjuncts to chemotherapy for cholangiocarcinoma.
MATERIALS AND METHODS:

We assessed the effect of purified green tea catechins on chemotherapy-induced apoptosis in KMCH, CC-LP-1 and Mz-ChA-1 human cholangiocarcinoma cells, and on chemosensitivity of Mz-ChA-1 cell xenografts in nude mice.
RESULTS:

Epigallocatechin-gallate (EGCG), but not the structurally related catechin epigallocatechin, sensitized cells to apoptosis induced by gemcitabine (GEM), mitomycin C or 5-fluorouracil in vitro. Mitochondrial membrane depolarization, cytosolic cytochrome c expression and apoptosis were increased in cells incubated with EGCG and GEM compared with either agent alone. Furthermore, EGCG decreased in vivo growth and increased the sensitivity to GEM of Mz-ChA-1 cell xenografts in nude mice.
CONCLUSIONS:

The green tea polyphenol EGCG sensitizes human cholangiocarcinoma cells to chemotherapy-induced apoptosis and warrants evaluation as an adjunct to chemotherapy for the treatment of human cholangiocarcinoma.

Nanotechnology. 2011 May 27;22(21):215101. Epub 2011 Mar 30.
Green tea extract selectively targets nanomechanics of live metastatic cancer cells.

Cross SE, Jin YS, Lu QY, Rao J, Gimzewski JK.

LINK

Source

Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA. California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.

Abstract

Green tea extract (GTE) is known to be a potential anticancer agent (Yang et al 2009 Nat. Rev. Cancer 9 429-39) with various biological activities (Lu et al 2005 Clin. Cancer Res. 11 1675-83; Yang et al 1998 Carcinogenesis 19 611-6) yet the precise mechanism of action is still unclear. The biomechanical response of GTE treated cells taken directly from patient's body samples was measured using atomic force microscopy (AFM) (Binnig et al 1986 Phys. Rev. Lett. 56 930). We found significant increase in stiffness of GTE treated metastatic tumor cells, with a resulting value similar to untreated normal mesothelial cells, whereas mesothelial cell stiffness after GTE treatment is unchanged. Immunofluorescence analysis showed an increase in cytoskeletal-F-actin in GTE treated tumor cells, suggesting GTE treated tumor cells display mechanical, structural and morphological features similar to normal cells, which appears to be mediated by annexin-I expression, as determined by siRNA analysis of an in vitro cell line model. Our data indicates that GTE selectively targets human metastatic cancer cells but not normal mesothelial cells, a finding that is significantly advantageous compared to conventional chemotherapy agents.

Toxicol Lett. 2000 Apr 3;114(1-3):155-62.
Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.

Sadzuka Y, Sugiyama T, Sonobe T.

LINK

Source

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, Japan. sadzuka@ys7.u-shizuoka-ken.ac.jp

Abstract

Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity.

Food Chem Toxicol. 2011 Jun;49(6):1410-5. Epub 2011 Mar 31.
Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro.

Qiao J, Gu C, Shang W, Du J, Yin W, Zhu M, Wang W, Han M, Lu W.

LINK

Source

Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.

Abstract

Tea drinking is widely practiced in the world and has recently increased among cancer patients. However, the effects of concurrent consumption of tea on the bioavailability and the net therapeutic potential of co-administered chemical drugs are not clear. In this study, the effects of green tea on the pharmacokinetics of 5-fluorouracil (5-FU) in rats and the pharmacodynamics in human cell lines in vitro were studied. The pharmacokinetic experiment indicated that there was an approximately 151% increase in the maximum plasma concentration (C(max)) and an approximately 425% increase in the area under the plasma concentration curve (AUC) of 5-FU in the green tea-treated group compared with the control group. Green tea consumption increased the plasma concentration of 5-FU. In addition, the pharmacodynamics experiment showed that at the moderate dose level (equivalent to <6 cups daily in human), neither fresh green tea extract nor (-)-epigallocatechin-3-gallate (EGCG) showed significant additive effects on the cytotoxicity of 5-FU in human cell lines. The results showed that it is crucial to perform therapeutic drug monitoring (TDM) when the cancer patients have a habit of drinking green tea.
Copyright Â© 2011 Elsevier Ltd. All rights reserved.

J Mol Med (Berl). 2011 Jun;89(6):595-602. Epub 2011 Feb 18.
Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability.

Ge J, Tan BX, Chen Y, Yang L, Peng XC, Li HZ, Lin HJ, Zhao Y, Wei M, Cheng K, Li LH, Dong H, Gao F, He JP, Wu Y, Qiu M, Zhao YL, Su JM, Hou JM, Liu JY.
LINK

Source

Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Guo Xue Xiang, Chengdu, Sichuan Province, China.

Abstract

Sunitinib, a novel oral multi-targeted tyrosine kinase inhibitor for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumor, has a good prospect for clinical application and is being investigated for the potential therapy of other tumors. We observed the phenomenon that drinking tea interfered with symptom control in an mRCC patient treated with sunitinib and speculated that green tea or its components might interact with sunitinib. This study was performed to investigate whether epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib. The interaction between EGCG and sunitinib was examined in vitro and in vivo. (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy and mass spectrometry (MS) were used to analyze the interaction between these two molecules and whether a new compound was formed. Solutions of sunitinib and EGCG were intragastrically administered to rats to investigate whether the plasma concentrations of sunitinib were affected by EGCG. In this study, we noticed that a precipitate was formed when the solutions of sunitinib and EGCG were mixed under both neutral and acidic conditions. (1)H-NMR spectra indicated an interaction between EGCG and sunitinib, but no new compound was observed by MS. Sticky semisolid contents were found in the stomachs of sunitinib and EGCG co-administrated mice. The AUC(0-∞) and C (max) of plasma sunitinib were markedly reduced by co-administration of EGCG to rats. Our study firstly showed that EGCG interacted with sunitinib and reduced the bioavailability of sunitinib. This finding has significant practical implications for tea-drinking habit during sunitinib administration.

Front Biosci. 2007 Sep 1;12:4881-99.
Green tea polyphenols: biology and therapeutic implications in cancer.

Shankar S, Ganapathy S, Srivastava RK.
Department of Biochemistry, University of Texas Health Science Center at Tyler, Tyler, Texas 75703, USA.

FREE TEXT

Multiple lines of evidence, mostly from population-based studies, suggest that green tea consumption is associated with reduced risk of several human malignancies such as cancer and diabetes. Epigallocatechin-3-gallate (EGCG), a major polyphenol found in green tea, is a widely studied chemopreventive agent with potential anticancer activity. Green tea polyphenols inhibit angiogenesis and metastasis, and induce growth arrest and apoptosis through regulation of multiple signaling pathways. Specifically, EGCG regulates expression of VEGF, matrix metalloproteinases, uPA, IGF-1, EGFR, cell cycle regulatory proteins and inhibits NFk B, PI3-K/Akt, Ras/Raf/MAPK and AP-1 signaling pathways, thereby causing strong cancer chemopreventive effects. This review discusses the molecular mechanisms of green tea polyphenols and their therapeutic implications in cancer.

PMID: 17569617 [PubMed - indexed for MEDLINE]

Crit Rev Food Sci Nutr. 2009 May;49(5):463-73.
Green tea: nature's defense against malignancies.

Butt MS, Sultan MT.
National Institute of Food Science and Technology, University of Agriculture, Faisalabad. drmsbutt@yahoo.com
The current practice of introducing phytochemicals to support the immune system or fight against diseases is based on centuries old traditions. Nutritional support is a recent advancement in the domain of diet-based therapies; green tea and its constituents are one of the important components of these strategies to prevent and cure various malignancies. The anti-carcinogenic and anti-mutagenic activities of green tea were highlighted some years ago suggesting that it could reduce the prevalence of cancer and even provide protection. The pharmacological actions of green tea are mainly attributed to polyphenols that includes epigallocatechin-3-gallate (EGCG), epicatechin, epicatechin-3-gallate, epigallocatechin. Green tea and its components effectively mitigate cellular damage arising due to oxidative stress. Green tea is supposed to enhance humoral and cell-mediated immunity, decreasing the risk of certain cancers, and may have certain advantage in treating inflammatory disorders. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest, by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing nuclear factor kappa-B activation. Besides, it regulates and promotes IL-23 dependent DNA repair and stimulates cytotoxic T cells activities in a tumor microenvironment. It also blocks carcinogenesis by modulating the signal transduction pathways involved in cell proliferation, transformation, inflammation and metastasis. The review is intended to highlight the chemistry of green tea, its antioxidant potential, its immunopotentiating properties and mode of action against various cancer cell lines that showed its potential as a chemopreventive agent against colon, skin, lung, prostate, and breast cancer.

PMID: 19399671 [PubMed - indexed for MEDLINE]

Cancer Lett. 2007 Jan 8;245(1-2):232-41. Epub 2006 Mar 6.
Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells in vitro and in vivo.

Thangapazham RL, Singh AK, Sharma A, Warren J, Gaddipati JP, Maheshwari RK.
Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Tea [Camellia sinensis (Theaceae)] intake is second only to water in terms of worldwide popularity as a beverage. The Green tea polyphenols have been shown to have a protective effect in prostate cancer in various pre-clinical animal models and has been reported to be effective in several other cancer types as well. An inverse association between the risk of breast cancer and the intake of green tea has also been reported in Asian Americans. Several epidemiological studies have shown that breast cancer progression is delayed in the Asian population that consumes green tea on regular basis. In this study, we report the effectiveness of green tea polyphenols (GTP) and its constituent Epigallocatechin Gallate (EGCG) in tumor regression using both in-vitro cell culture models and in vivo athymic nude mice models of breast cancer. The anti-proliferative effect of GTP and EGCG on the growth of human breast cancer MDA-MB-231 cell was studied using a tetrazolium dye-based (MTT) assay. Both GTP and EGCG treatment had the ability to arrest the cell cycle at G1 phase as assessed by flow cytometry. The expression of Cyclin D, Cyclin E, CDK 4, CDK 1 and PCNA were down regulated over the time in GTP and EGCG treated experimental group, compared to the untreated control group as evaluated by western blot analysis for cell cycle proteins, which corroborated the G1 block. Nude mice inoculated with human breast cancer MDA-MB-231 cells and treated with GTP and EGCG were effective in delaying the tumor incidence as well as reducing the tumor burden when compared to the water fed and similarly handled control. GTP and EGCG treatment were also found to induce apoptosis and inhibit the proliferation when the tumor tissue sections were examined by immunohistochemistry. Our results suggest that GTP and EGCG treatment inhibits proliferation and induce apoptosis of MDA-MB-231 cells in-vitro and in-vivo. All together, these data sustain our contention that GTP and EGCG have anti-tumor properties.

PMID: 16519995 [PubMed - indexed for MEDLINE]

Mol Cancer Ther. 2006 May;5(5):1227-38.
Green tea extract and (-)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells.

Zhang Q, Tang X, Lu Q, Zhang Z, Rao J, Le AD.
Division of Surgical, Therapeutic and Bioengineering Sciences, Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Health Sciences Campus, 2250 Alcazar Street, CSA103, Los Angeles, CA 90033, USA.
Green tea extract and its major component (-)-epigallocatechin-3-gallate (EGCG) exhibit antiangiogenic activities in various experimental tumor models. A growing body of evidence has established that hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream target, vascular endothelial growth factor (VEGF), play a critical role in tumor angiogenesis. In this study, we investigated the effect of green tea extract and EGCG on HIF-1alpha and VEGF expression in human cervical carcinoma (HeLa) and hepatoma (HepG2) cells. Our results showed that green tea extract and EGCG significantly inhibited hypoxia- and serum-induced HIF-1alpha protein accumulation in these cancer cells but had no effects on HIF-1alpha mRNA expression. Suppression of HIF-1alpha protein by green tea extract and EGCG also resulted in a drastic decrease in VEGF expression at both mRNA and protein levels. The mechanisms of green tea extract and EGCG inhibition of hypoxia-induced HIF-1alpha protein accumulation seem to involve the blocking of both phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 signaling pathways and the enhancing of HIF-1alpha protein degradation through the proteasome system. In addition, green tea extract and EGCG inhibited serum-induced HIF-1alpha protein and VEGF expression by interfering with the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathways, which play a crucial role in the protein translational machinery cascade. Functionally, green tea extract and EGCG abolished both chemoattractant- and hypoxia-stimulated HeLa cell migration. Our data suggested that HIF-1alpha/VEGF function as therapeutic target for green tea extract and EGCG in the context of cancer chemoprevention and anticancer therapy.

PMID: 16731755 [PubMed - indexed for MEDLINE]

Clin Cancer Res. 2009 Dec 15;15(24):7608-7615.
Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity.

Puig T, Turrado C, BenhamÃº B, Aguilar H, Relat J, Ortega-GutiÃ©rrez S, Casals G, Marrero PF, Urruticoechea A, Haro D, LÃ³pez-RodrÃ*guez ML, Colomer R.
Authors' Affiliations: Institut CatalÃ* d'Oncologia and Institut d'InvestigaciÃ³ BiomÃ¨dica de Girona, BioquÃ*mica i Biologia Molecular, Facultat de CiÃ¨ncies, Universitat de Girona, Girona, Spain; QuÃ*mica OrgÃ¡nica I, Facultad de Ciencias QuÃ*micas, Universidad Complutense de Madrid, M.D. Anderson Cancer Center EspaÃ±a, Madrid, Spain; Institut CatalÃ* d'Oncologia and Institut d'InvestigaciÃ³ BiomÃ¨dica de Bellvitge, and BioquÃ*mica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain.
PURPOSE: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (-)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models.Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. EXPERIMENTAL DESIGN: We evaluated the in vitro effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells. RESULTS: Interestingly, the compounds did not stimulate CPT-1 activity in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo. CONCLUSIONS: The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with in vitro and in vivo anticancer activity, that do not exhibit cross-activation of beta-oxidation and do not induce weight loss in animals. One of the compounds blocked the growth of breast cancer xenografts. These FASN inhibitors may represent new agents for breast cancer treatment. (Clin Cancer Res 2009;15(24):7608-15).

PMID: 20008854 [PubMed - as supplied by publisher]

Cancer Res. 2007 Oct 1;67(19):9018-23.
Trastuzumab-resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate.

Eddy SF, Kane SE, Sonenshein GE.
Department of Biochemistry and Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA
Overexpression of the epidermal growth factor receptor family member HER2 is found in approximately 30% of breast cancers and is a target for immunotherapy. Trastuzumab, a humanized monoclonal antibody against HER2, is cytostatic when added alone and highly successful in clinical settings when used in combination with other chemotherapeutic agents. Unfortunately, HER2 tumors in patients develop resistance to trastuzumab or metastasize to the brain, which is inaccessible to antibody therapy. Previously, we showed that the green tea polyphenol epigallocatechin-3 gallate (EGCG) inhibits growth and transformed phenotype of Her-2/neu-driven mouse mammary tumor cells. The different modes of action of EGCG and trastuzumab led us to hypothesize that EGCG will inhibit HER2-driven breast cancer cells resistant to trastuzumab. We studied trastuzumab-resistant BT474 human breast cancer cells, isolated by chronic trastuzumab exposure, and JIMT-1 breast cancer cells, derived from a pleural effusion in a patient who displayed clinical resistance to trastuzumab therapy. EGCG treatment caused a dose-dependent decrease in growth and cellular ATP production, and apoptosis at high concentrations. Akt activity was suppressed by EGCG leading to the induction of FOXO3a and target cyclin-dependent kinase inhibitor p27Kip1 levels. Thus, EGCG in combination with trastuzumab may provide a novel strategy for treatment of HER2-overexpressing breast cancers, given that EGCG can cross the blood-brain barrier.

PMID: 17909003 [PubMed - indexed for MEDLINE]

Breast Cancer Res. 2010 Jan 15;12(1):R8. [Epub ahead of print]
(-)-Epigallocatechin gallate sensitizes breast cancer cells to paclitaxel in a murine model of breast carcinoma.

Luo T, Wang J, Yin Y, Hua H, Jing J, Sun X, Li M, Zhang Y, Jiang Y.
ABSTRACT: INTRODUCTION: Paclitaxel (Taxol(R)) is a microtubule-targeted agent that is widely used for cancer treatment. However, resistance to paclitaxel is frequently encountered in the clinic. There is increasing interest in identifying compounds that may increase the sensitivity to conventional chemotherapeutic agents. In this study, we investigated whether green tea polyphenol (-)-epigallocatechin gallate (EGCG) can sensitize breast carcinoma to paclitaxel in vivo. METHODS: Breast cancer cells were treated with or without EGCG and paclitaxel followed by detection of cell survival and apoptosis. c-Jun NH2-terminal kinase (JNK) phosphorylation and glucose regulated protein 78 (GRP78) expression were detected by Western blotting. For in vivo study, 4T1 breast cancer cells were inoculated into Balb/c mice to establish a syngenic transplantation model. The tumor-bearing mice were treated with or without EGCG (30mg/kg, i.p.) and paclitaxel (10mg/kg, i.p.). Tumor growth was monitored. Apoptosis in tumor tissues was detected. Cell lysates from tumors were subjected to Western blot analysis of GRP78 expression and JNK phosphorylation. RESULTS: EGCG synergistically sensitized breast cancer cells to paclitaxel in vitro and in vivo. EGCG in combination with paclitaxel significantly induced 4T1 cells apoptosis compared with each single treatment When tumor-bearing mice were treated with paclitaxel in combination with EGCG, tumor growth was significantly inhibited, whereas the single-agent activity for paclitaxel or EGCG was poor. EGCG overcame paclitaxel -induced GRP78 expression and potentiated paclitaxel -induced JNK phosphorylation in 4T1 cells both in vitro and in vivo. CONCLUSIONS: EGCG may be used as a sensitizer to enhance the cytotoxicity of paclitaxel.

PMID: 20078855 [PubMed - as supplied by publisher]

Urol Oncol. 2008 Sep 23. [Epub ahead of print]
Taxol synergizes with antioxidants in inhibiting hormal refractory prostate cancer cell growth.

Ping SY, Hour TC, Lin SR, Yu DS.
Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Taxanes are chemotherapeutic agents commonly used to treat various carcinomas. Dietary antioxidants, such as vitamin E, green tea extracts, and isoflavones have been used against prostate cancer, and exhibit anticancer effects both in vitro and in vivo. We evaluated the combined effect of taxol (paclitaxel) with pyrrolidine dithiocarbamate, vitamin E, epigallocatechin gallate, and genistein in killing hormone-refractory prostate cancer cells. Those agents were tested on the hormone-refractory prostate cancer cell line PC-3, and the viability of the cells was determined using MTT {3 (4, 5-dimethylthiazo-2-yl)-2, 5-diphenyl tetrazolium} assay after drug treatment. PC-3 cells were sensitive to these drugs with 50% inhibitory concentrations of 0.1, 23, 220, 1122, and 260 muM, for taxol, pyrrolidine dithiocarbamate, epigallocatechin gallate, genistein, and vitamin E, respectively. Genistein, pyrrolidine dithiocarbamate, and epigallocatechin gallate showed synergistic cytotoxicity to PC-3 cells when combined with 0.01 muM taxol. Only high concentration of vitamin E showed a synergistic effect with this dose of taxol. Further study revealed that 3 combinations could induce sub-G1 phase of cell cycle, induce apoptosis, and increase caspase activity and decrease Bcl-2 expression simultaneously. In conclusion, in addition to vitamin E, incorporation of these antioxidants with taxan-based cytotoxic therapies offers encouraging strategies for combating hormone-refractory prostate cancers.

PMID: 18818108 [PubMed - as supplied by publisher]

Volume 269, Issue 2, Pages 269-280 (8 October 2008)
Multitargeted therapy of cancer by green tea polyphenols

Received 20 February 2008; received in revised form 20 February 2008; accepted 9 April 2008. published online 23 May 2008.
LINK

Abstract

Tea ranks second only to water as a major component of fluid intake worldwide and has been considered a health-promoting beverage since ancient times. For the past two decades, we and others have been investigating the potential cancer preventive and therapeutic effects of green tea and its polyphenolic mixture termed GTP. It has become clear that much of these effects of GTP are mediated by its most abundant catechin, epigallocatechin gallate (EGCG). Large amount of encouraging data from in vitro and animal models has emerged making clear that green tea is a natureâ€™s gift molecule endowed with anticancer effects. Epidemiological and geographical observations suggest that these laboratory data may be applicable to human population. Clinical trials of GTP, especially in prostate cancer patients have yielded encouraging results. This article briefly reviews properties of GTP, especially EGCG with reference to multitargeted therapy of cancer.

Corresponding author. Tel.: +1 608 263 3927; fax: +1 608 263 5223.

Rejuvenation Res. 2006 Spring;9(1):45-55.
Catechin-vanilloid synergies with potential clinical applications in cancer.

MorrÃ© DM, MorrÃ© DJ.
Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana 47907-2059, USA. morredm@purdue.edu
A cancer-specific cell surface protein, tNOX, has been identified as a target for low-dose cell killing (apoptosis) of cancer cells by green tea catechins and Capsicum vanilloid combinations. This protein is uniquely associated with all forms of cancer and is absent from normal cells and tissues. Its activity is correlated with cancer growth. When blocked, cancer cells fail to enlarge after division and eventually die. Among the most potent and effective inhibitors of tNOX are naturally occurring polyphenols exemplified by the principal green tea catechin (-)-epigallocatechin gallate (EGCg) and the vanilloid capsaicin. Catechin-vanilloid combinations are 10 to 100 times more effective than either catechins or vanilloids alone. Vector-forced overexpression of tNOX cDNA and antisense has demonstrated that the tNOX target is both necessary and sufficient to explain the anticancer properties of green tea catechins alone and in vanilloid-containing combinations. The necessity and sufficiency of tNOX was validated as the catechin target with transgenic mice overexpressing the processed form of tNOX. Transgenic mice grew faster and the increased growth caused by tNOX overexpression was blocked by EGCg in the drinking water. A catechin-vanilloid mixture where one 350-mg capsule is equivalent to 16 cups of green tea in its ability to inhibit tNOX and growth of cancer cells in culture is undergoing clinical evaluation as a therapeutic aid for cancer patients.

PMID: 16608395 [PubMed - indexed for MEDLINE]

J Nutr. 2004 Aug;134(8):1948-52.
Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice.

Lambert JD, Hong J, Kim DH, Mishin VM, Yang CS.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA. joshua_lambert@hotmail.com
(-)-Epigallocatechin-3-gallate (EGCG), from green tea (Camellia sinensis), has demonstrated chemopreventive activity in animal models of carcinogenesis. Previously, we reported the bioavailability of EGCG in rats (1.6%) and mice (26.5%). Here, we report that cotreatment with a second dietary component, piperine (from black pepper), enhanced the bioavailability of EGCG in mice. Intragastric coadministration of 163.8 micromol/kg EGCG and 70.2 micromol/kg piperine to male CF-1 mice increased the plasma C(max) and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. Piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100 micromol/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%) but not in hepatic microsomes. Piperine (20 micromol/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C(max) = 37.50 +/- 22.50 nmol/g at 60 min that then decreased to 5.14 +/- 1.65 nmol/g at 90 min; however, cotreatment with piperine resulted in a C(max) = 31.60 +/- 15.08 nmol/g at 90 min, and levels were maintained above 20 nmol/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4621.80 +/- 1958.72 vs. 1686.50 +/- 757.07 (nmol/g.min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone. The present study demonstrates the modulation of the EGCG bioavailablity by a second dietary component and illustrates a mechanism for interactions between dietary chemicals.

PMID: 15284381 [PubMed - indexed for MEDLINE]

Nutr Res. 2009 Nov;29(11):784-93.
Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet.

Chen N, Bezzina R, Hinch E, Lewandowski PA, Cameron-Smith D, Mathai ML, Jois M, Sinclair AJ, Begg DP, Wark JD, Weisinger HS, Weisinger RS.
Department of Optometry and Vision Sciences, University of Melbourne, Australia.
The mechanisms of how tea and epigallocatechin-3-gallate (EGCG) lower body fat are not completely understood. This study investigated long-term administration of green tea (GT), black tea (BT), or isolated EGCG (1 mg/kg per day) on body composition, glucose tolerance, and gene expression related to energy metabolism and lipid homeostasis; it was hypothesized that all treatments would improve the indicators of metabolic syndrome. Rats were fed a 15% fat diet for 6 months from 4 weeks of age and were supplied GT, BT, EGCG, or water. GT and BT reduced body fat, whereas GT and EGCG increased lean mass. At 16 weeks GT, BT, and EGCG improved glucose tolerance. In the liver, GT and BT increased the expression of genes involved in fatty acid synthesis (SREBP-1c, FAS, MCD, ACC) and oxidation (PPAR-alpha, CPT-1, ACO); however, EGCG had no effect. In perirenal fat, genes that mediate adipocyte differentiation were suppressed by GT (Pref-1, C/EBP-beta, and PPAR-gamma) and BT (C/EBP-beta), while decreasing LPL, HSL, and UCP-2 expression; EGCG increased expression of UCP-2 and PPAR-gamma genes. Liver triacylglycerol content was unchanged. The results suggest that GT and BT suppressed adipocyte differentiation and fatty acid uptake into adipose tissue, while increasing fat synthesis and oxidation by the liver, without inducing hepatic fat accumulation. In contrast, EGCG increased markers of thermogenesis and differentiation in adipose tissue, while having no effect on liver or muscle tissues at this dose. These results show novel and separate mechanisms by which tea and EGCG may improve glucose tolerance and support a role for these compounds in obesity prevention.

PMID: 19932867 [PubMed - in process]

J Nutr. 2006 Oct;136(10):2512-8.
Epigallocatechin gallate supplementation alleviates diabetes in rodents.

Wolfram S, Raederstorff D, Preller M, Wang Y, Teixeira SR, Riegger C, Weber P.
DSM Nutritional Products Ltd, Department of Human Nutrition and Health, CH-4002 Basel, Switzerland. swen.wolfram@dsm.com
As the prevalence of type 2 diabetes mellitus is increasing at an alarming rate, effective nutritional and exercise strategies for the prevention of this disease are required. Specific dietary components with antidiabetic efficacy could be one aspect of these strategies. This study investigated the antidiabetic effects of the most abundant green tea catechin, epigallocatechin gallate (EGCG, TEAVIGO), in rodent models of type 2 diabetes mellitus and H4IIE rat hepatoma cells. We assessed glucose and insulin tolerance in db/db mice and ZDF rats after they ingested EGCG. Using gene microarray and real-time quantitative RT-PCR we investigated the effect of EGCG on gene expression in H4IIE rat hepatoma cells as well as in liver and adipose tissue of db/db mice. EGCG improved oral glucose tolerance and blood glucose in food-deprived rats in a dose-dependent manner. Plasma concentrations of triacylglycerol were reduced and glucose-stimulated insulin secretion was enhanced. In H4IIE cells, EGCG downregulated genes involved in gluconeogenesis and the synthesis of fatty acids, triacylgycerol, and cholesterol. EGCG decreased the mRNA expression of phosphoenolpyruvate carboxykinase in H4IIE cells as well as in liver and adipose tissue of db/db mice. Glucokinase mRNA expression was upregulated in the liver of db/db mice in a dose-dependent manner. This study shows that EGCG beneficially modifies glucose and lipid metabolism in H4IIE cells and markedly enhances glucose tolerance in diabetic rodents. Dietary supplementation with EGCG could potentially contribute to nutritional strategies for the prevention and treatment of type 2 diabetes mellitus.

PMID: 16988119 [PubMed - indexed for MEDLINE]

Mol Pharmacol. 2010 Jan;77(1):17-25. Epub 2009 Oct 14.
Epigallocatechin-3-gallate inhibits osteoclastogenesis by down-regulating c-Fos expression and suppressing the nuclear factor-kappaB signal.

Lee JH, Jin H, Shim HE, Kim HN, Ha H, Lee ZH.
Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongro-Gu, Seoul 110-749, Republic of Korea.
Epigallocatechin-3-gallate (EGCG), the major anti-inflammatory compound in green tea, has been shown to suppress osteoclast differentiation. However, the precise molecular mechanisms underlying the inhibitory action of EGCG in osteoclastogenesis and the effect of EGCG on inflammation-mediated bone destruction remain unclear. In this study, we found that EGCG inhibited osteoclast formation induced by osteoclastogenic factors in bone marrow cell-osteoblast cocultures but did not affect the ratio of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL) to osteoprotegerin induced by osteoclastogenic factors in osteoblasts. We also found that EGCG inhibited osteoclast formation from bone marrow macrophages (BMMs) induced by macrophage colony-stimulating factor plus RANKL in a dose-dependent manner without cytotoxicity. Pretreatment with EGCG significantly inhibited RANKL-induced the gene expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. EGCG suppressed RANKL-induced activation of c-Jun N-terminal protein kinase (JNK) pathway, among the three well known mitogen-activated protein kinases and also inhibited RANKL-induced phosphorylation of the NF-kappaB p65 subunit at Ser276 and NF-kappaB transcriptional activity without affecting the degradation of IkappaBalpha and NF-kappaB DNA-binding in BMMs. The inhibitory effect of EGCG on osteoclast formation was somewhat reversed by retroviral c-Fos overexpression, suggesting that c-Fos is a downstream target for antiosteoclastogenic action of EGCG. In addition, EGCG treatment reduced interleukin-1-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo. Taken together, our data suggest that EGCG has an antiosteoclastogenic effect by inhibiting RANKL-induced the activation of JNK/c-Jun and NF-kappaB pathways, thereby suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

PMID: 19828731 [PubMed - indexed for MEDLINE]

Rich66 · 03-06-2010, 06:54 PM

Possible Liver issues in extremely high (1500 mg per kg) doses:

doi:10.1016/j.fct.2009.10.030

Copyright Â© 2009 Elsevier Ltd All rights reserved.

Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice

purchase

Joshua D. Lambert^a^,^,, Mary J. Kennett^b, Shengmin Sang^c, Kenneth R. Reuhl^d, Jihyeung Ju^e^,¹ and Chung S. Yang^e

^a Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, USA
^b Department of Veterinary Sciences, The Pennsylvania State University, University Park, PA 16802, USA
^c Human Nutrition Program, Biomedical/Biotechnology Research Institute, North Carolina Central University, Kannapolis, NC 28081, USA
^d Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
^e Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

Received 20 May 2009;
accepted 25 October 2009.
Available online 31 October 2009.

Abstract

The tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case-reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice. A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg, i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and γ-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein-1. Our results indicate that higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages.

In Vivo. 2005 Jan-Feb;19(1):179-83.
In vivo antitumor effect of ascorbic acid, lysine, proline and green tea extract on human prostate cancer PC-3 xenografts in nude mice: evaluation of tumor growth and immunohistochemistry.

Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.
Matthias Rath Research, Cancer Division, Santa Clara, CA 95050, USA.
BACKGROUND: Matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), Ki 67 (proliferative protein) and constituents of ECM play a critical role in angiogenesis, and are crucial in neoplastic invasion and metastasis. Based on the antitumor properties of certain nutrients, we investigated the effect of a diet containing lysine, proline, arginine, ascorbic acid and green tea extract on the growth of tumors induced by implanting human prostate cancer PC-3 cells in athymic nude mice and on the expression of MMPs, VEGF, Ki 67 and fibronectin in these tumors, as well as the production of mucin (by PAS staining). MATERIALS AND METHODS: Male nude mice (n =12) were inoculated with 3x10(6) prostate cancer PC-3 cells and randomly divided into two groups; Group A was fed a regular diet and Group B was fed a regular diet supplemented with 0.5% of the nutrient mixture (NM). Four weeks later, tumors were excised, weighed and processed for histology. RESULTS: The results showed inhibition of tumor growth in Group B. Histological studies revealed inhibition of MMP-9 and VEGF secretion and mitosis in Group B tissues. CONCLUSION: Nutrient supplementation strongly suppressed the growth of tumors without any adverse effects in nude mice, suggesting strong potential as an anticancer agent.

PMID: 15796171 [PubMed - indexed for MEDLINE]

Invest New Drugs. 2009 Nov 20. [Epub ahead of print]
Inhibitory effects of tea polyphenols by targeting cyclooxygenase-2 through regulation of nuclear factor kappa B, Akt and p53 in rat mammary tumors.

Roy P, George J, Srivastava S, Tyagi S, Shukla Y.
Proteomics Laboratory, Indian Institute of Toxicology Research, CSIR, Mahatma Gandhi Marg, Lucknow, 226001, India.
Breast cancer has become the second leading cause of cancer-related deaths worldwide. The control of this disease can be achieved through chemoprevention, which refers to the consumption of synthetic or naturally occurring agents to block, reverse, or delay the process of tumor development. Tea (Camellia sinensis), the most widely consumed beverage, has shown promises in the field of cancer chemoprevention. Inhibition of tumorigenesis by green or black tea polyphenols has been demonstrated in various in vitro and in vivo models. Here, we examined the inhibitory effect of green tea polyphenol (GTP) and black tea polyphenol (BTP) on the development of mammary tumors- induced by 7, 12-dimethylbenz (a) anthracene (DMBA) in female, Wistar rats. 13% and 33% of animals developed tumors in GTP and BTP supplemented groups, respectively. Both GTP and BTP are effective in significantly inhibiting the cumulative number of mammary tumors (by ~92% and 77%, respectively) and in reducing their growth. Mechanistically, we investigated the effects of GTP and BTP on the components of cell signaling pathways, connecting biomolecules involved in cancer development. GTP and BTP supplementation as a sole source of drinking solution leads to scavenging of reactive oxygen species (ROS) (by ~72% and 69%, respectively) by inhibiting cyclooxygenase-2 (Cox-2) and inactivation of phosphorylated forms of nuclear factor-kappa B (NF-kappaB) and Akt. Altogether, the study suggests that both cultivars of tea, i.e. green and black, have anti-tumorigenic potential against DMBA-induced mammary tumorigenesis in Wistar rats. Further studies such as large and long term cohort studies and clinical trials are warranted.

PMID: 19936622 [PubMed - as supplied by publisher]

Phytomedicine. 2010 Apr;17(5):356-362. Epub 2010 Feb 10.
(-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line.

Farabegoli F, Papi A, Bartolini G, Ostan R, Orlandi M.
Department of Experimental Pathology, Via San Giacomo, 14, University of Bologna, 40126 Bologna, Italy.
We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100mug/ml for 24-72hours) caused cell growth inhibition and dose-dependent apoptosis: after 100mug/ml EGCG treatment for 24hours, Bax expression increased and Bcl2 expression decreased (p<0.05). Coherently, Annexin V-FITC apoptosis assay detected a significant increase in labelled cells (p<0.05). EGCG did not affect MRP1: in contrast, 100mug/ml EGCG administration caused P-gp decrease to 53% of control cells (p<0.001) and this effect was not due to downregulation of P-gp gene expression. EGCG induced P-gp decrease even when MG132, a strong proteasome inhibitor, was given together with EGCG to MCF-7Tam cells. EGCG treatment also inhibited BCRP activity: mRNA transcription and protein level did not change after treatment, but mitoxantrone test demonstrated a strong inhibition of BCRP activity (p<0.001). In conclusion, the present results showed that EGCG could down-regulate the activity of two molecules that play a key role in drug metabolism and transport and that are highly expressed in tamoxifen resistant breast carcinoma cells. The interaction of EGCG and drugs used in the therapy of estrogen sensitive breast carcinoma ought to be subject of studies and the potential use of EGCG in drug-resistant diseases ought to be better considered. Copyright Â© 2010 Elsevier GmbH. All rights reserved.

PMID: 20149610 [PubMed - as supplied by publisher]

Epigallocatechin Gallate Dose-Dependently Induces Apoptosis or Necrosis in Human MCF-7 Cells

YAN-DER HSUUW ^a AND WEN-HSIUNG CHAN ^b ^a Department of Life Science, National Pingtung University of Science and Technology, Pingtung, Taiwan 912 ^b Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, Taiwan 32023
Address for correspondence: Wen-Hsiung Chan, Department of Bioscience Technology, Chung Yuan Christian University, Chung Li, Taiwan 32023. Voice: +886-3-2653515; fax: +886-3-2653599.
e-mail: whchan@cycu.edu.tw

Copyright 2007 New York Academy of Sciences

KEYWORDS
catechin . EGCG . apoptosis . necrosis . oxidative stress

ABSTRACT

Abstract : The catechins, a family of polyphenols found in tea, can evoke various responses, including cell death. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that treatment of human MCF-7 cells with 50 μM (-)-Epigallocatechin-3-gallate (EGCG), a catechin that is highly abundant in green tea, can induce apoptotic changes, including mitochondrial membrane potential changes and activation of c-Jun N-terminal kinase (JNK), caspase-9, and caspase-3. In contrast, higher concentrations of EGCG (100-400 μM) do not induce apoptosis, but rather trigger necrotic cell death in MCF-7 cells. Investigations of the possible mechanisms underlying these differences revealed that treatment with lower concentrations of EGCG (10-50 μM) directly increased intracellular oxidative stress, while higher concentrations (100-400 μM) did not. Immunoblotting revealed that treatment of MCF-7 cells with 10-50 μM EGCG caused increases in Bax protein levels and decreases in Bcl-2 protein levels, shifting the Bax-Bcl-2 ratio to favor apoptosis, while treatment with 100-400 μM EGCG had no such effect. Moreover, we observed a dose-dependent decrease in intracellular ATP levels in cells treated with high-dose EGCG. Blockade of reactive oxygen species (ROS) generation and ATP synthesis using antioxidants and ATP synthesis inhibitors revealed that ROS and ATP play important roles to switch cell death types with apoptosis or necrosis. Collectively, these results indicate for the first time that EGCG treatment has a dose-dependent effect on ROS generation and intracellular ATP levels in MCF-7 cells, leading to either apoptosis or necrosis, and that the apoptotic cascade involves JNK activation, Bax expression, mitochondrial membrane potential changes, and activation of caspase-9 and caspase-3.

DIGITAL OBJECT IDENTIFIER (DOI)
10.1196/annals.1397.046 About DOI

Acta Biochim Biophys Sin (Shanghai). 2009 Dec 15;41(12):1018-26.
Potentiation of (-)-epigallocatechin-3-gallate-induced apoptosis by bortezomib in multiple myeloma cells.

Wang Q, Li J, Gu J, Huang B, Zhao Y, Zheng D, Ding Y, Zeng L.
Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
The green tea constituent, (-)-epigallocatechin-3-gallate (EGCG), has chemopreventive and anticancer effects. This is partially because of the selective ability of EGCG to induce apoptosis and death in cancer cells without affecting normal cells. In the present study, the activity of EGCG against the myeloma cell line, KM3, was examined. Our results demonstrated, for the first time, that the treatment of the KM3 cell line with EGCG inhibits cell proliferation and induces apoptosis, and there is a synergistic effect when EGCG and bortezomib are combined. Further experiments showed that this effect involves the NF-kappaB pathway. EGCG inhibits the expression of the P65 mRNA and P65/pP65 protein, meanwhile it downregulates pIkappaBalpha expression and upregulates IkappaBalpha expression. EGCG also activates caspase-3, -8, cleaved caspase-9, and poly-ADP-ribose polymerase (PARP) and subsequent apoptosis. These findings provided experimental evidence for efficacy of EGCG alone or in combination with bortezomib in multiple myeloma therapy.

PMID: 20011976 [PubMed - in process]

Cancer Sci.. [Epub ahead of print]
(-)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein.

Luo KL, Luo JH, Yu YP.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
(-)-Epigallocatechin-3-gallate (EGCG) is one of the major polyphenol components in green tea. It effectively induces apoptosis in prostate cancer cells. The anticancer effect of this reagent is appealing because it is a natural component of a popular daily beverage that has proven harmless for thousands of years, making it a good candidate chemopreventive agent. EGCG suppresses cell growth and causes cell death, but the mechanisms are not well characterized, especially in androgen-independent prostate cancer cells. In the present study, using Affymetrix genechip Hu133 2.0, we analyzed the gene expression patterns of the androgen-independent prostate cancer cell line Du145, treated with or without EGCG, and found 40 genes whose expression levels were altered (>twofold, either upregulated or downregulated, P < 0.01) upon treatment with EGCG. These gene products are involved in the functions of transcription, RNA processing, protein folding, phosphorylation, protein degradation, cell motility, and ion transport. Among them, inhibitor of DNA binding 2 (ID2), known as a dominant anti-retinoblastoma (Rb) helix-loop-helix protein, was found to be downregulated fourfold by EGCG treatment. Forced expression of ID2 in Du145 cells reduced apoptosis and increased cell survival in the presence of EGCG, and knockdown ID2 expression in Du145 cells using a morpholino oligonucleotide specific for ID2 mimicked the apoptosis effect generated by EGCG treatment, although it was milder. To our knowledge, this is the first report indicating that ID2 is one of the critical factors in the signaling pathway of Du145 cell death induced by EGCG. (Cancer Sci 2009).

PMID: 20002680 [PubMed - as supplied by publisher]

Breast Cancer, Chemotherapy, & Antioxidants

BY JOHANNA ALTGELT & MICHAEL McCULLOCH
INTRODUCTION
LINK

Quote:

Green Tea Polyphenols
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.
In a laboratory study from China, it was demonstrated that green tea polyphenol improved effectiveness of Adriamycin in estrogen receptor-positive breast cancer cells that had become resistant to adriamycin treatment (Zhu and Wang, 2001).
Â» Green Tea Polyphenols (EGCG): One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

J Diet Suppl. 2008 Nov 1;5(3):248-263.
Pharmacokinetics of Green Tea Catechins in Extract and Sustained-Release Preparations.

Janle EM, MorrÃ© DM, MorrÃ© DJ, Zhou Q, Zhu Y.
Botanical Center In Vivo Core, Purdue University, Department of Foods and Nutrition, West Lafayette, IN.
Catechins are a major constituent of green tea. For green tea to have cancer therapeutic benefit, catechin concentrations in the range of 100 nM are required continuously until apoptosis (programmed cell death) is induced. To prolong elevated plasma and interstitial concentrations of catechins, a sustained-release formulation of green tea extract was tested and compared to a commercial green tea extract (Tegreen97((R))). Sustained-release formulations are usually developed in the pharmaceutical industry to slowly deliver the compound over a period of time and increase the dosing interval. Plasma and interstitial fluid (ISF) pharmacokinetics of catechins were determined following an oral dose in the rat. The sustained-release formulation profile included multiple smaller peaks of total catechins in both plasma and ISF. Interstitial fluid profiles of green tea extract indicate that higher catechins concentration and longer duration in tissue than in blood may make a sustained-release form unnecessary.

PMID: 19885387 [PubMed]

Tegreen alternative formula
http://www.nuskin.com/nuskin/us/en/p.../01003529.html

Rasberry seed formulation proposed as higher potency form of EGCG:
http://www.ellagic.net/ellagic-acid-fraud.html
beware of the claims of percentage Ellagic Acid content. It is only the Ellagitannin content that is relevant.
"The Ellagic Acid compound is much stronger and biologically active then the tannins found in green teas."

J Cell Mol Med. 2008 Nov 6. [Epub ahead of print]
Synergistic promotion of breast cancer cells death by targeting molecular chaperone GRP78 and heat shock protein 70.

Li M, Wang J, Jin J, Hua H, Luo T, Xu L, Wang R, Liu D, Jiang Y.
Division of Signal Transduction and Molecular Targeting Therapy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Abstract Heat shock protein 70 (HSP70) is frequently overexpressed in a variety of human malignancies and protects cancer cells against apoptosis in response to various stresses. The bioflavonoid quercetin inhibits HSP70 expression and induces cancer cells apoptosis. In the present study, we investigated the effects of HSP70 down-regulation on the unfolded protein response and addressed a novel strategy to enhance the proapoptotic effect of quercetin by suppressing GRP78 induction simultaneously. Treatment of human breast cancer cells with quercetin down-regulates HSP70 expression, but up-regulates GRP78 expression in a dose-dependent manner. Down-regulation of HSP70 by small interfering RNA also leads to induction of GRP78. Moreover, our studies reveal that HSP70 knockdown or quercetin induces other typical components of the unfolded protein response, including CHOP expression, eIF2a and JNK phosphorylation, caspases activation, and XBP-1 splicing. Abrogating the induction of pro-survival chaperone GRP78 by small interfering RNA sensitizes breast cancer cells to quercetin. Colony survival assays demonstrate that treatment of breast cancer cells with green tea (-)-epigallocatechin gallate (EGCG), which binds to the ATP-binding domain of GRP78 and blocks its protective function, synergistically promoted quercetin-induced cell death. These studies reveal that HSP70 downregulation leads to the induction of unfolded protein response. The pro-survival GRP78 induction contributes to quercetin resistance. Abrogation of GRP78 induction or inhibition of GRP78 activity increases the effectiveness of quercetin. These findings indicate that combinational administration of flavonoids capable of suppressing HSP70 and GRP78 such as quercetin and EGCG might represent a novel approach for cancer therapy or chemoprevention.

PMID: 19017364 [PubMed - as supplied by publisher]

Int J Oncol. 2007 Apr;30(4):963-9. Links: Combined effect of green tea and Ganoderma lucidum on invasive behavior of breast cancer cells.

Thyagarajan A, Zhu J, Sliva D.
Cancer Research Laboratory, Methodist Research Institute, E504, Indianapolis, IN 46202, USA.
Epidemiological studies have suggested that consumption of green tea may decrease the risk of a variety of cancers. In addition, mushroom Ganoderma lucidum has been used for the promotion of health, longevity and treatment of cancer in traditional Chinese medicine. In the present study we show that extract from green tea (GTE) increased the anticancer effect of G. lucidum extract (GLE) on cell proliferation (anchorage-dependent growth) as well as colony formation (anchorage-independent growth) of breast cancer cells. This effect was mediated by the down-regulation of expression of oncogene c-myc in MDA-MB-231 cells. Although individual GTE and GLE independently inhibited adhesion, migration and invasion of MDA-MB-231 cells, their combination demonstrated a synergistic effect, which was mediated by the suppression of secretion of urokinase plasminogen activator (uPA) from breast cancer cells. Our study suggests the potential use of combined green tea and G. lucidum extracts for the suppression of growth and invasiveness of metastatic breast cancers.

Green Tea treatment and links:
http://www.nutraingredients.com/Rese...-tea-treatment

http://www.defense.gov/transformation/articles/2006-05/ta050306a.html

Researchers Discover Possible Anti-Cancer Treatment Researchers at the U.S. Army Natick Soldier Center and the University of
Massachusetts-Lowell unexpectedly discovered a potential anti-cancer treatment.

The effectiveness that is being shown is "incredible" according to Dr. Ferdinando Bruno, research chemist, Natick Soldier Center
"The catechin oligomer compounds have been shown to be effective in killing breast, stomach and neck cancer cells, in tissue culture, with approximately 90, 75 and 50 percent inhibition, respectively." Dr. Ferdinando Bruno, research chemist

Dr. Lynne Samuelson, a research chemist from Natick Soldier Center and a pioneer of enzymatic template polymerization, suggested increasing the water solubility of these novel compounds by tethering them to a large molecule called polystyrene sulfonate.
This templated reaction made the naturally occurring catechin oligomer longer lived and more water soluble, but the modified compound was still not effective against cancer cells at doses that could be administered to humans.
Jayant Kumar, director of the Center for Advanced Materials at University of Massachusetts -Lowell, then suggested adding ethanol, an alcohol, to try to make the compound more efficient. While growing up, Bruno attended Jesuit schools in Italy.
He remembered the fountains in the schools' cafeterias filled with both water and wine and suggested adding 10 percent ethanol to the solution, which appears to be the correct combination.
This was a key to the development of the new anti-carcinogens and made these new compounds effective at very low doses.

With increased stability and effectiveness, this family of compounds is now being tested for its efficacy against a wide variety of different human cancers by another University of Massachusetts collaborator, Dr. Susan J. Braunhut, and her team.

http://nsrdec.natick.army.mil/LIBRARY/00-09/R08-86.pdf
Article
Biocatalytically Oligomerized Epicatechin with Potent and Specific Anti-proliferative Activity for Human Breast Cancer Cells
Subhalakshmi Nagarajan 1,6, Ramaswamy Nagarajan 2, Susan J. Braunhut 3,
Ferdinando Bruno 4
,
Donna McIntosh 3, Lynne Samuelson 4 and Jayant Kumar 5,6,*
1 Department of Chemistry, University of Massachusetts, Lowell, USA
2 Department of Plastics Engineering, University of Massachusetts, Lowell, USA
3 Department of Biological Sciences, University of Massachusetts, Lowell, USA
4 U.S Army Natick Soldier Research, Development & Engineering Center, Natick, MA, 01760
5 Department of Physics, University of Massachusetts, Lowell, USA
6 Center for Advanced Materials, University of Massachusetts, Lowell, USA
* Author to whom correspondence should be addressed. E-mail: Jayant_Kumar@uml.edu.
Received: 18 August 2008; in revised form: 26 September 2008 / Accepted: 7 October 2008 /
Published: 1 November 2008
Abstract: Catechins, naturally occurring flavonoids derived from wine and green tea, are known to exhibit multiple health benefits. Epigallocatechin gallate (EGCG) is one of the most widely investigated catechins, but its efficacy in cancer therapy is still inconsistent and limited. The poor stability of EGCG has contributed to the disparity in the reported anti-cancer activity and other beneficial properties. Here we report an innovative enzymatic strategy for the oligomerization of catechins (specifically epicatechin) that yields stable, water-soluble oligomerized epicatechins with enhanced and highly specific anti-proliferative activity for human breast cancer cells. This one-pot oxidative oligomerization is carried out in ambient conditions using Horseradish Peroxidase (HRP) as a catalyst yielding water-soluble oligo(epicatechins). The oligomerized epicatechins obtained exhibit excellent growth inhibitory effects against human breast cancer cells with greater specificity towards growth-inhibiting cancer cells as opposed to normal cells, achieving a high therapeutic differential. Our studies indicate that water-soluble oligomeric epicatechins surpass EGCG in stability, selectivity and efficacy at lower doses.

Search results on researcher: HERE

her1, her2 and her 3

They synthesized compounds similar to those in curcumin, green tea, soy genistein--compound 2e which they synthesized blocked her1,2, and 3 signalling which the natural compounds couldn't do as effectively

Since these are artificial compounds , a drug co. may get interested in finding out best dose, schedulling, which patients best to target, etc

Chembiochem. 2010 Jan 7. [Epub ahead of print]
Unnatural Polyketide Analogues Selectively Target the HER Signaling Pathway in Human Breast Cancer Cells.
Kwon SJ, Kim MI, Ku B, Coulombel L, Kim JH, Shawky JH, Linhardt RJ, Dordick JS.

Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180 (USA), Fax: (+1) 5182762207.
Receptor tyrosine kinases are critical targets for the regulation of cell survival. Cancer patients with abnormal receptor tyrosine kinases (RTK) tend to have more aggressive disease with poor clinical outcomes. As a result, human epidermal growth factor receptor kinases, such as EGFR (HER1), HER2, and HER3, represent important therapeutic targets. Several plant polyphenols including the type III polyketide synthase products (genistein, curcumin, resveratrol, and epigallocatechin-3-galate) possess chemopreventive activity, primarily as a result of RTK inhibition. However, only a small fraction of the polyphenolic structural universe has been evaluated. Along these lines, we have developed an in vitro route to the synthesis and subsequent screening of unnatural polyketide analogues with N-acetylcysteamine (SNAc) starter substrates and malonyl-coenzyme A (CoA) and methylmalonyl-CoA as extender substrates. The resulting polyketide analogues possessed a similar structural polyketide backbone (aromatic-2-pyrone) with variable side chains. Screening chalcone synthase (CHS) reaction products against BT-474 cells resulted in identification of several trifluoromethylcinnamoyl-based polyketides that showed strong suppression of the HER2-associated PI3K/AKT signaling pathway, yet did not inhibit the growth of nontransformed MCF-10A breast cells (IC(50)>100 muM). Specifically, 4-trifluoromethylcinnamoyl pyrone (compound 2 e) was highly potent (IC(50)<200 nM) among the test compounds toward proliferation of several breast cancer cell lines. This breadth of activity likely stems from the ability of compound 2 e to inhibit the phosphorylation of HER1, HER2, and HER3. Therefore, these polyketide analogues might prove to be useful drug candidates for potential breast cancer therapy.

PMID: 20058253 [PubMed - as supplied by publisher]

Br J Haematol. 2010 Jan 20. [Epub ahead of print]
Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2.

Britschgi A, Simon HU, Tobler A, Fey MF, Tschan MP.
Department of Clinical Research, Experimental Oncology/Haematology, University of Bern, Bern, Switzerland.
Summary Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.

PMID: 20096012 [PubMed - as supplied by publisher]

Chem Biol Interact. 2010 Mar 24. [Epub ahead of print]
(-)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells.

Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Kubota M, Adachi S, Tsurumi H, Hara Y, Moriwaki H.
Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
(-)-Epigallocatechin gallate (EGCG), the major constituent of green tea, inhibits the growth of colorectal cancer cells by inhibiting the activation of various types of receptor tyrosine kinases (RTKs). The RTK vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis induces tumor angiogenesis in colorectal cancer. This study examined the effects of EGCG on the activity of the VEGF/VEGFR axis and the expression of hypoxia-inducible factor (HIF)-1alpha, which promotes angiogenesis by elevating VEGF levels, in human colorectal cancer cells. Total and phosphorylated (i.e., activated) form (p-VEGFR-2) of VEGFR-2 proteins were overexpressed in a series of human colorectal cancer cell lines. Within 3hours, EGCG caused a decrease in the expression of HIF-1alpha protein and VEGF, HIF-1alpha, insulin-like growth factor (IGF)-1, IGF-2, epidermal growth factor (EGF), and heregulin mRNAs in SW837 colorectal cancer cells, which express a constitutively activated VEGF/VEGFR axis. A decrease was also observed in the expression of VEGFR-2, p-VEGFR-2, p-IGF-1 receptor, p-ERK, and p-Akt proteins within 6hours after EGCG treatment. Drinking EGCG significantly inhibited the growth of SW837 xenografts in nude mice, and this was associated with the inhibition of the expression and activation of VEGFR-2. The consumption of EGCG also inhibited activation of ERK and Akt, both of which are downstream signaling molecules of the VEGF/VEGFR axis, and reduced the expression of VEGF mRNA in xenografts. These findings suggest that EGCG may exert, at least in part, growth-inhibitory effects on colorectal cancer cells by inhibiting the activation of the VEGF/VEGFR axis through suppressing the expression of HIF-1alpha and several major growth factors. EGCG may therefore be useful in the chemoprevention and/or treatment of colorectal cancer. Copyright Â© 2010. Published by Elsevier Ireland Ltd.

PMID: 20346928 [PubMed - as supplied by publisher]

J Surg Res. 2007 Jul;141(1):115-9.
Dietary influence on pancreatic cancer growth by catechin and inositol hexaphosphate.

McMillan B, Riggs DR, Jackson BJ, Cunningham C, McFadden DW.
Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, West Virginia, USA.
Abstract

INTRODUCTION: Pancreatic cancer is an extremely virulent form of cancer with few effective treatments. We hypothesized that, alone and in combination, IP6 and catechin would be effective against pancreatic cancer. MATERIALS AND METHODS: Pancreatic (PANC-1 and MIAPACA) cancer cell lines were cultured and treated with IP6 (0.8 mM/well), catechin (100 microM/well), and the combination of the two. Cell viability was measured by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) at 24, 48, and 72 h. Vascular endothelial growth factor (VEGF) was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC). RESULTS: Catechin and inositol hexaphosphate (IP6), two naturally occurring molecules found in green tea and high-fiber foods, respectively, are compounds that have been shown to demonstrate anti-proliferative effects when administered as single therapeutic agents against a number of cancers.The combination of catechin and IP6 significantly inhibited proliferation in the PANC-1 cell line at 24, 48, and 72 h compared to single agents (P < 0.001). Growth of the MIAPACA cell line was inhibited (P < 0.01) by each agent alone, but additive inhibitory effects were not seen. An increase in early apoptosis was attributed to catechin therapy in both cell lines (P < 0.01). The combination of these agents also increased early apoptotic activity when compared to the control (P < 0.001). IP6 reduced VEGF in both cell lines (P < 0.01). In combination, catechin and IP6 amplified VEGF reduction compared to each agent in MIAPACA and control (P < 0.002). CONCLUSIONS: These results, combined with the prevalence of these compounds in safe, naturally occurring foods, make catechin and IP6 attractive therapies for treatment, and possibly in preventative trials, of pancreatic cancer.

PMID: 17574044 [PubMed - indexed for MEDLINE]

Rich66 · 03-06-2010, 09:32 PM

Telomerase related to cancer stem cell issues:

Int J Oncol. 2004 Mar;24(3):703-10.
EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to suppression of cell viability and induction of apoptosis.

Mittal A, Pate MS, Wylie RC, Tollefsbol TO, Katiyar SK.
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Telomerase is elevated in >90% of breast carcinomas and therefore has received much attention as a target for breast cancer therapy and cancer diagnostic research. Dietary components that are capable of inhibiting the growth of cancer cells without affecting the growth of normal cells are receiving considerable attention in developing novel cancer-preventive approaches. Studies have shown that (-)-epigallocatechin-3-gallate (EGCG) from green tea imparts a growth inhibitory effect on cancer cells. Here, we show that treatment of EGCG dose-dependently inhibited (20-100%) the reproductive or colony forming potential, and also decreased cell viability at different time points studied ( approximately 80% inhibition) in human breast carcinoma MCF-7 cells but had no adverse effect on the growth of normal mammary cells. Treatment of EGCG for 48 and 72 h markedly increased the percentage of apoptotic cells (32-51%) in MCF-7 cells compared to that of non-EGCG treated cells (8-14%). In order to identify the possible mechanism of decreased cell viability and induction of apoptosis in breast carcinoma cells by EGCG, we found that treatment of MCF-7 cells with EGCG dose-dependently inhibited telomerase activity (40-55%), and also inhibited the mRNA expression (40-55%) of hTERT, a catalytic subunit of telomerase. Additional studies demonstrated that EGCG also inhibited the protein expression of hTERT, which indicated that inhibition of telomerase was associated with down-regulation of hTERT. Together, our results indicate that EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to the suppression of cell viability and induction of apoptosis, thus providing the molecular basis for the development of EGCG as a novel chemopreventive and pharmacologically safe agent against breast cancer.

PMID: 14767556 [PubMed - indexed for MEDLINE]

Cancer Lett. 2006 May 8;236(1):80-8. Epub 2005 Jun 21.
The tea polyphenols EGCG and EGC repress mRNA expression of human telomerase reverse transcriptase (hTERT) in carcinoma cells.

Lin SC, Li WC, Shih JW, Hong KF, Pan YR, Lin JJ.
Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Li-Nong St, Sec., 2, No155, Peitou, Taipei 112, Taiwan, ROC. sclin@ym.edu.tw
Tea polyphenols have inhibitive effects for carcinogenesis. A reporter system controlled by hTERT promoter was constructed to evaluate the effects of tea polyphenols, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epigallocatechin (EGC) on the repression of hTERT transcription. The hTERT promoter activity was selectively repressed by 20-40 microM EGCG and EGC in a dose- and time-dependent manner. Real-time RT-PCR confirmed that the endogenous hTERT mRNA level was decreased in H1299, OECM-1 and SAS cells treated with EGCG or EGC. Our results identified the repression activities of EGCG and EGC toward telomerase expression that might be linked to inhibition of carcinoma cell growth. This cell-based reporter system is useful for screening drugs targeting hTERT repression.

PMID: 15975707 [PubMed - indexed for MEDLINE]

Mol Biol Rep. 2009 May;36(5):1181-6. Epub 2008 Jun 26.
The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin.

Shervington A, Pawar V, Menon S, Thakkar D, Patel R.
Brain Tumour North West, Faculty of Science, University of Central Lancashire, Preston, UK. aashervington@uclan.ac.uk
Telomerase expression strongly correlates with the grade of malignancy in glioma with inhibition illustrating a definite increase in chemosensitivity. This study was designed to investigate the effects of a green tea derivative, epigallocatechin-3-gallate (EGCG); together with either cisplatin or tamoxifen in glioma, and to investigate whether these effects are mediated through telomerase suppression. EGCG showed a significant cytotoxic effect on 1321N1 cells after 24 h and on U87-MG cells after 72 h (P < 0.001) without significantly affecting the normal astrocytes. Treatment with EGCG inhibited telomerase expression significantly (P < 0.01) and enhanced the effect of cisplatin and tamoxifen in both 1321N1 (P < 0.01) and U87-MG (P < 0.001) cells. EGCG, as a natural product has enormous potential to be an anti-cancer agent capable of enhancing tumour cell sensitivity to therapy.

PMID: 18581255 [PubMed - indexed for MEDLINE]

Cancer Detect Prev. 2007;31(6):499-504.
(-)-Epigallocatechin-3-gallate downregulates estrogen receptor alpha function in MCF-7 breast carcinoma cells.

Farabegoli F, Barbi C, Lambertini E, Piva R.
Department of Experimental Pathology, University of Bologna, V.S. Giacomo 14, 40126 Bologna, Italy. fulvia.farabegoli@unibo.it
BACKGROUND: (-)-Epigallocatechin-3-gallate (EGCG) is the most active catechin present in green tea, demonstrated to have chemopreventive action and to kill cancer cells selectively. As a previous study found that catechins could compete with 17-beta-estradiol for binding to estrogen receptor alpha (ERalpha), we asked whether EGCG could regulate ERalpha action. METHODS: We used MCF-7, a breast carcinoma cell line having a high level of ERalpha expression. The cells were treated with various EGCG concentrations and cell viability was evaluated by MTT assay. ERalpha and pS2 expression were analyzed by RT-PCR after RNA extraction. To better define EGCG action in relation to ERalpha, we studied EGCG cytotoxicity on MCF-7 resistant to tamoxifen (MCF-7tam), MCF-7 treated with 10(-7)M ICI 182,780 for 8 days and on MDA-MB-231, a cell line that lacked ERalpha by flow cytometry (FCM). RESULTS: Both ERalpha and pS2 mRNA were expressed in samples treated with low EGCG concentration (30 microg/ml). At this concentration, no cell change was detectable. In contrast, pS2 expression was lost in samples treated with 100 microg/ml EGCG for 24h, indicating ERalpha alteration. EGCG cytotoxicity was lower when ERalpha was not present (MDA-MB-231) or inactivated (by tamoxifen or ICI 182,780). CONCLUSIONS: Functionally active ERalpha may have a role in EGCG cytotoxicity, increasing the sensitivity to the drug. As higher EGCG concentrations also killed cells resistant to tamoxifen or treated by 10(-7)M ICI 182,780, EGCG ought to be better investigated in breast carcinoma cells treated with drugs targeted to steroid receptors, as a potential complement of therapy.

PMID: 18061364 [PubMed - indexed for MEDLINE]

Carcinogenesis. 2006 Dec;27(12):2424-33. Epub 2006 Jun 19.
The combination of green tea and tamoxifen is effective against breast cancer.

Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, Sartippour G, Zhang L, Lu M, Weinberg O, Rao JY, Brooks MN.
Department of Surgery, Center for Human Nutrition, University of California, Los Angeles, CA 90095-1782, USA.
Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention.

PMID: 16785249 [PubMed - indexed for MEDLINE]

Anticancer Drugs. 2004 Oct;15(9):889-97.
Tamoxifen and epigallocatechin gallate are synergistically cytotoxic to MDA-MB-231 human breast cancer cells.

Chisholm K, Bray BJ, Rosengren RJ.
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
High concentrations of specific catechins [epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG)] inhibit the proliferation of many different cancer cell lines. The aim of this work was to determine if low concentrations of catechins with and without 4-hydroxytamoxifen (4-OHT) co-treatment would cause significant cytotoxicity in estrogen receptor-positive (ERalpha+) and -negative (ERalpha-) human breast cancer cells. Therefore, MCF-7, T47D, MDA-MB-231 and HS578T cells were incubated with EGCG, EGC or ECG (5-25 microM) individually and in combination with 4-OHT for 7 days. Cell number was determined by the sulforhodamine B cell proliferation assay. As single agents, none of the catechins were cytotoxic to T47D cells, while only EGCG (20 microM) elicited cytotoxicity in MCF-7 cells. Additionally, no benefit was gained by combination treatment with 4-OHT. ERalpha- human breast cancer cells were more susceptible as all three catechins were significantly cytotoxic to HS578T cells at concentrations of 10 microM. In this cell line, combination with 4-OHT did not increase cytotoxicity. However, the most striking results were produced in MDA-MB-231 cells. In this cell line, EGCG (25 microM) produced a greater cytotoxic effect than 4-OHT (1 microM) and the combination of the two resulted in synergistic cytotoxicity. In conclusion, low concentrations of catechins are cytotoxic to ERalpha- human breast cancer cells, and the combination of EGCG and 4-OHT elicits synergistic cytotoxicity in MDA-MB-231 cells.

PMID: 15457130 [PubMed - indexed for MEDLINE]

J Biochem Mol Biol. 2005 Sep 30;38(5):563-70.
Hepatoprotective effect of green tea (Camellia sinensis) extract against tamoxifen-induced liver injury in rats.

El-Beshbishy HA.
Biochemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt. Hesham_Elbeshbishy@hotmail.com
Tamoxifen citrate (TAM), is widely used for treatment of breast cancer. It showed a degree of hepatic carcinogenesis. The purpose of this study was to elucidate the antioxidant capacity of green tea (Camellia sinensis) extract (GTE) against TAM-induced liver injury. A model of liver injury in female rats was done by intraperitoneal injection of TAM in a dose of 45mg Kg(-1) day(-1), i.p. for 7 successive days. GTE in the concentration of 1.5 %, was orally administered 4 days prior and 14 days after TAM-intoxication as a sole source of drinking water. The antioxidant flavonoid; epicatechin (a component of green tea) was not detectable in liver and blood of rats in either normal control or TAM-intoxicated group, however, TAM intoxication resulted in a significant decrease of its level in liver homogenate of tamoxifenintoxicated rats. The model of TAM-intoxication elicited significant declines in the antioxidant enzymes (glutathione-S-transferase,glutathione peroxidase, superoxide dismutase and catalase) and reduced glutathione concomitant with significant elevations in TBARS (thiobarbituric acid reactive substance) and liver transaminases; sGPT (serum glutamate pyruvate transaminase) and sGOT (serum glutamate oxaloacetate transaminase) levels. The oral administration of 1.5 % GTE to TAM-intoxicated rats, produced significant increments in the antioxidant enzymes and reduced glutathione concomitant with significant decrements in TBARS and liver transaminases levels. The data obtained from this study speculated that 1.5 % GTE has the capacity to scavenge free radical and can protect against oxidative stress induced by TAM intoxication. Supplementation of GTE could be useful in alleviating tamoxifen-induced liver injury in rats.

PMID: 16202236 [PubMed - indexed for MEDLINE]

Cancer Detect Prev. 2000;24(1):91-9.
A new concept of tumor promotion by tumor necrosis factor-alpha, and cancer preventive agents (-)-epigallocatechin gallate and green tea--a review.

Fujiki H, Suganuma M, Okabe S, Sueoka E, Suga K, Imai K, Nakachi K.
Saitama Cancer Center Research Institute, Kitaadachi-gun, Japan.
The study of tumor promotion in rodent carcinogenesis using chemical tumor promoters has revealed various tumor promotion pathways, such as the 12-O-tetradecanoylphorbol-13-acetate (TPA) pathway mediated through activation of protein kinase C, and the okadaic acid pathway mediated through inhibition of protein phosphatases 1 and 2A (PP-1 and PP-2A). We previously demonstrated that application of TPA and okadaic acid induced tumor necrosis factor-alpha (TNF-alpha) gene expression in mouse skin, but that tautomycin, which is an inhibitor of PP-1 and PP-2A and not a tumor promoter on mouse skin, did not. Moreover, we found that TNF-alpha stimulated transformation of BALB/3T3 cells initiated with 3-methylcholanthrene 1,000 times stronger than did TPA (Cancer Res. 53, 1982-1985, 1993). This evidence demonstrates a link between the okadaic acid pathway and the endogenous tumor promotion pathway of TNF-alpha. Recently we presented the first evidence that tumor promotion in TNF-alpha(-/-) mice was significantly depressed compared with TNF-alpha(+/+) mice. Thus, in human carcinogenesis, we think that TNF-alpha and other inflammatory cytokines in preneoplastic lesion stimulate tumor promotion and progression of initiated cells as well as premalignant cells. The first part of this paper reports on this TNF-alpha tumor promotion pathway. In the second part, we report a promising screening method for cancer preventive agents, based on evidence that pretreatment with agents such as tamoxifen, sulindac, 1alpha, 25-(OH)2 vitamin D3, quercetin, caffeic acid phenethyl ester, and (-)-epigallocatechin gallate (EGCG) commonly inhibited TNF-alpha release from BALB/3T3 cells induced by okadaic acid. EGCG, the main constituent of Japanese green tea, and green tea itself are acknowledged cancer preventives in Japan, and this paper presents evidence of their effectiveness in both a high-risk group and the general population.

PMID: 10757128 [PubMed - indexed for MEDLINE]

J Surg Res. 2007 Jul;141(1):115-9.
Dietary influence on pancreatic cancer growth by catechin and inositol hexaphosphate.

McMillan B, Riggs DR, Jackson BJ, Cunningham C, McFadden DW.
Department Of Surgery, Robert C. Byrd Health Science Center, West Virginia University, Morgantown, West Virginia, USA.
Abstract

INTRODUCTION: Pancreatic cancer is an extremely virulent form of cancer with few effective treatments. We hypothesized that, alone and in combination, IP6 and catechin would be effective against pancreatic cancer. MATERIALS AND METHODS: Pancreatic (PANC-1 and MIAPACA) cancer cell lines were cultured and treated with IP6 (0.8 mM/well), catechin (100 microM/well), and the combination of the two. Cell viability was measured by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) at 24, 48, and 72 h. Vascular endothelial growth factor (VEGF) was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC). RESULTS: Catechin and inositol hexaphosphate (IP6), two naturally occurring molecules found in green tea and high-fiber foods, respectively, are compounds that have been shown to demonstrate anti-proliferative effects when administered as single therapeutic agents against a number of cancers.The combination of catechin and IP6 significantly inhibited proliferation in the PANC-1 cell line at 24, 48, and 72 h compared to single agents (P < 0.001). Growth of the MIAPACA cell line was inhibited (P < 0.01) by each agent alone, but additive inhibitory effects were not seen. An increase in early apoptosis was attributed to catechin therapy in both cell lines (P < 0.01). The combination of these agents also increased early apoptotic activity when compared to the control (P < 0.001). IP6 reduced VEGF in both cell lines (P < 0.01). In combination, catechin and IP6 amplified VEGF reduction compared to each agent in MIAPACA and control (P < 0.002). CONCLUSIONS: These results, combined with the prevalence of these compounds in safe, naturally occurring foods, make catechin and IP6 attractive therapies for treatment, and possibly in preventative trials, of pancreatic cancer.

PMID: 17574044 [PubMed - indexed for MEDLINE]

Pharm Res. 2010 Jun;27(6):1103-14. Epub 2010 Mar 16.
Anti-melanoma effects of vorinostat in combination with polyphenolic antioxidant (-)-epigallocatechin-3-gallate (EGCG).

Nihal M, Roelke CT, Wood GS.
Department of Dermatology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Room B25, Madison, Wisconsin 53706, USA.
Abstract

PURPOSE: Melanoma is an aggressive neoplasm with a propensity for metastases and resistance to therapy. Previously, we showed that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present in green tea, resulted in a significant decrease in the viability and growth of melanoma and induction of apoptosis via modulation of the cki-cdk-cyclin network and Bcl2 family proteins. Epigenetic regulation of gene transcription by histone deacetylase (HDAC) inhibitors is gaining momentum as a novel cancer therapy. SAHA-suberoylanilidine hydroxamic acid Zolinza (vorinostat) is the first HDAC inhibitor approved by the U.S. FDA. In this study, we determined if vorinostat alone or in combination with EGCG imparts anti-proliferative effects against human melanoma cells. METHODS: Employing human melanoma cell lines A-375, Hs-294T and G-361, we determined the effect of vorinostat and/or EGCG on 1) growth/viability and colony formation, 2) apoptosis, and 3) the critical molecules involved in cell cycle and apoptosis regulation. RESULTS: Our data demonstrated that the anti-proliferative effects of vorinostat were greater than or similar to those of EGCG among the cell lines tested. Furthermore, relative to monotherapy, the combination treatment resulted in significantly greater inhibition of cell proliferation, increased apoptosis, activation of p21, p27 and caspases (3, 7 and 9) and Bax as well as down-regulation of cdk2, cdk4, cyclin A, NF-kappaB protein p65/RelA and Bcl2 protein and transcript. CONCLUSIONS: Our preclinical findings suggest that combination therapy with EGCG and vorinostat may be beneficial for the management of human melanoma.

PMID: 20232120 [PubMed - in process]

Cell Cycle. 2009 Jul 1;8(13):2057-63. Epub 2009 Jul 27.
(-)-Epigallocatechin-3-gallate (EGCG) sensitizes melanoma cells to interferon induced growth inhibition in a mouse model of human melanoma.

Nihal M, Ahsan H, Siddiqui IA, Mukhtar H, Ahmad N, Wood GS.
Department of Dermatology, University of Wisconsin Medical School and William S. Middleton VA Medical Center, Madison, WI 53706, USA.
Comment in:

Cell Cycle. 2009 Jul 1;8(13):1979-80.

Abstract

Melanoma incidence has increased over the last few decades and metastatic melanoma is one of the hardest malignancies to treat. Thus, novel approaches are needed for an effective management of melanoma. Interferon-alpha2b (IFN), an immunomodulatory cytokine commonly used in melanoma treatment, has shown marginal efficacy and often results in discontinuation of therapy due to toxicity. We earlier demonstrated that epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, caused cell cycle arrest and apoptosis of human melanoma cells via modulation in cki-cyclin-cdk machinery and Bcl-2 family proteins. This study was undertaken to determine if EGCG could enhance the anti-proliferative effects of IFN. In this study, we demonstrated that EGCG and/or IFN treatments to melanoma cells resulted in a marked (1) decrease in cell proliferation and colony formation ability, and (2) induction of apoptosis. Interestingly, the combination was found to be more effective than either of the agents alone. Further, the anti-proliferative effects of EGCG and/or IFN were accompanied with an increase in Fas protein levels and a decrease in nuclear factor NFkappaB/p65 in the nucleus as well as NFkappaB promoter activity. EGCG and/or IFN also resulted in an increase in Fas-L mediated apoptosis. Further, EGCG and/or IFN treatments resulted in a decrease in melanoma tumor growth and protein levels of proliferation marker PCNA, in athymic nude mice implanted with melanoma tumors. The combination of the two modalities demonstrated a better response than either of them alone. Our data suggest that EGCG could impart therapeutic advantage if used in conjunction with IFN.

PMID: 19502799 [PubMed - indexed for MEDLINE]

Photomed Laser Surg. 2010 May 3. [Epub ahead of print]
Extraordinary Anticancer Effect of Green Tea and Red Light.

Sommer AP, Zhu D, Scharnweber T.
1 Institute of Micro and Nanomaterials, University of Ulm , Ulm, Germany .

Abstract

Abstract Objective: Increasing observational evidence suggests that epigallocatechin gallate-the major polyphenolic component of green tea-is instrumental in suppressing the growth of cancer cells. Therefore, methods that promise to enhance the suppressive potential of green tea have the highest clinical relevance. Background Data: Human cervical cancer cells, HeLa, the first continuous cancer cell line, represent a mainstay model in cancer research. Green tea inhibited their growth, whereas their exposure to moderate levels of laser light resulted in an opposite effect. Both effects are individually documented in the literature. Methods: HeLa cells were supplemented with green tea, irradiated with moderately intense laser light (670 nm) for 1 min, and incubated for 52 h. Results: We found an extraordinary inhibition of HeLa cells by a combination of green tea and red light. We achieved an inhibition of 1,460%, compared with non-irradiated samples. Conclusion: Our result receives clinical relevance from a recent study in which epigallocatechin gallate suppressed the growth of melanoma in vivo.

PMID: 20438353 [PubMed - as supplied by publisher]

TanyaRD · 02-01-2011, 10:02 AM

Rich,
There is one study that "stopped us in our tracks" so to speak in regards to green tea and I have pasted it below. Prior to this study I highly recommended green tea to my patients during treatment. This study caused all of us to examine that recommendation and the decision was made to have patients avoid large amounts of green tea (occasional cup ok) and none for those on Velcade. This was a difficult decision to make and possibly over cautious but one we felt justified until further evidence is available to provide assurance that there will be no interaction/decreased efficacy when used in conjunction with chemotherapy.

Blood. 2009 Jun 4;113(23):5927-37. Epub 2009 Feb 3.
Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.

Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, SchÃ¶nthal AH.
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089-9094, USA.
Comment in

Rich66 · 02-01-2011, 12:30 PM

From the abstract:

Quote:

antagonistic function of EGCG was evident only with boronic acid-based proteasome inhibitors (BZM, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir).

From the paper:

Quote:

The severe antagonistic effect of EGCG appeared to require thepresence of the boronic acid moiety in BZM. Among the 6 proteasomeinhibitors tested, the boronic acid–containing ones (BZM,MG-262, PS-IX) were similarly incapacitated by EGCG, whereasnone of those without this functional group (NFV, MG-132, PS-I)were affected by EGCG. In this context, it is noteworthy thatthe chemical structures of MG-262 (effective inhibition by EGCG)and MG-132 (no inhibition by EGCG) differ only in the presence/absenceof the boronic acid moiety (Figure 4A), indicating that thedecisive mechanism of EGCG's antagonism resides with the chemicalstructure of the target molecule (ie, the boronic acid moiety),not its function (ie, proteasome inhibition).

Seems like a potential issue for a class within a class of chemo...demonstrated in two cancers other than BC.

But along the dietary line, those in this narrow category may have a number of things to avoid:
http://bloodjournal.hematologylibrar...ll/113/24/6262

Quote:

In addition, since this appearsto be a class effect (ie, boronic acid–based drugs willlikely bind polyphenols with similar structures), we suggestthat other food products that contain high concentrations ofpolyphenols, such as berries, red wine, walnuts, peanuts, andpomegranates, should also be avoided by patients who are receivingbortezomib