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DNC News
The Top Green Tea Extracts: updated August 2004
Carcinogenesis. 2004 Aug 12 [Epub ahead of print] Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells.
Baek SJ, Kim JS, Jackson FR, Eling TE, McEntee MF, Lee SH.
Laboratory of Environmental Carcinogenesis, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996.
There is persuasive epidemiological and experimental evidence that dietary polyphenolic plant-derived compounds have anti-cancer activity. Many laboratories, including ours, have reported such an effect in cancers of the gastrointestinal tract, lung, skin, prostate, and breast. The catechins are a group of polyphenols found in green tea, which is one of the most commonly consumed beverages in the world. While the preponderance of the data strongly indicates significant anti-tumorigenic benefits from the green tea catechins, the potential molecular mechanisms involved remain obscure. We found that green tea components induce apoptosis via a TGF-beta superfamily protein, NAG-1 (Nonsteroidal anti-inflammatory drug Activated Gene). In this report, we show that ECG is the strongest NAG-1 inducer among the tested catechins and that treatment of HCT-116 cells results in an increasing G1 sub-population, and cleavage of poly (ADP-ribose) polymerase (PARP), consistent with apoptosis. In contrast, other catechins do not significantly induce NAG-1 expression, PARP cleavage or morphological changes at up to 50 micro M concentration. Furthermore, we provide evidence that ECG induces the ATF3 transcription factor, followed by NAG-1 induction at the transcriptional level in a p53 independent manner. The data generated by this study will help elucidate mechanisms of action for components in green tea and this information may lead to the design of more effective anti-cancer agents and informed clinical trials.
PMID: 15308587 [PubMed - as supplied by publisher]
Asia Pac J Clin Nutr. 2004;13(Suppl):S116. Green tea consumption enhances survival of epithelial ovarian cancer patients.
Binns CW, Zhang M, Lee AH, Xie CX.
School of Public Health, Curtin University of Technology GPO Box U 1987, Perth 6845, Western Australia.
Aim: To investigate whether green tea consumption post-diagnosis can enhance survival of patients with epithelial ovarian cancer. Methods: A prospective cohort study was conducted in the community, Hangzhou , P. R. China. A cohort of 309 patients with histopathologically confirmed epithelial ovarian cancer, who were recruited in the study during 1999-2000, were followed for a minimum of three years. The variables measured included their survival time and the frequency and quantity of tea consumed post diagnosis. From the original cohort 294 (95.1%) subjects, or their close relatives, were traced and interviewed using a structured questionnaire in 2003. The actual number of deaths was obtained and the hazard ratios were calculated. Cox proportional models were used to compute adjusted hazard ratios (HR) and associated 95% confidence intervals (CI). These models were adjusted for age at diagnosis, locality, BMI, parity, stage at diagnosis, histo-pathologic grade of differentiation, cytology of ascites, and the presence of residual tumor after surgery. Results: Increasing frequency and quantity of tea consumption were associated a longer survival in Chinese women with epithelial ovarian cancer. The survival experiences were different between tea drinkers and non-drinkers (p <0.001). There were 109 (79.6%) out of 137 tea-drinkers who survived to the time of interview, compared with only 77 women (49.0%) still alive among the 157 non-tea drinkers. Compared with non-drinkers, the adjusted hazard ratios were 0.6 (95% CI 0.4-0.9) for tea-drinkers, 0.3 (95% CI 0.2-0.8) for consuming at least one cup of green tea per day, 0.4 (95%CI 0.2-0.8) for brewing at least one batch of green tea per day, and 0.3 (95% CI 0.2-0.8) for consumption of 500 grams or more dried tealeaf per year. The corresponding dose response relationships were statistically significant. Conclusion: Regular consumption of green tea post-diagnosis can enhance epithelial ovarian cancer survival. There are no previously published studies of ovarian cancer survival and tea consumption. This study has the potential to benefit many women who are diagnosed with ovarian cancer.
PMID: 15294648 [PubMed - in process] J Herb Pharmcother. 2003;3(3):19-32. Analysis of Catechin Content of Commercial Green Tea Products.
Manning J, Roberts JC.
Salt Lake City , UT , 54112-5820 , USA .
Tea (Camellia sinensis) contains numerous polyphenolic flavonoid-derived compounds known as catechins, which have shown interesting protective activity against cancer and cardiovascular disease. Numerous products based on tea are commercially available, many of which claim to contain specific amounts of the bioactive catechins. The catechin content of seven commercial green tea products (encapsulated extracts or tea bags) was quantified by HPLC and, where possible, compared to that claimed on the label. Wide variability was observed in the catechin content between green tea products, even those that appear outwardly similar to consumers. Measured catechin content ranged from 9% to 48% of label claims; all values were significantly lower than those claims (P < 0.05). These results continue to demonstrate the problems that exist with quality control in the dietary supplement and herbal medicine industry and, there, for consumers of nutraceuticals.
PMID: 15277054 [PubMed - as supplied by publisher] Nutr Rev. 2004 May;62(5):204-11. Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials.
Moyers SB, Kumar NB.
Department of Cancer Control and Nutrition, H. Lee Moffitt Cancer Center and Research Institute, Tampa , Florida , USA .
Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials.
Publication Types: • Review • Review, Tutorial
PMID: 15212320 [PubMed - indexed for MEDLINE]
Cancer Chemother Pharmacol. 2004 Aug 7 [Epub ahead of print] Phase I study of green tea extract in patients with advanced lung cancer.
Laurie SA, Miller VA, Grant SC, Kris MG, Ng KK.
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Avenue, 10126, New York, NY, USA.
PURPOSE. Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer. METHODS. A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m(2) per day, with an accelerated dose-escalation scheme. RESULTS. On this schedule, the MTD of GTE was 3 g/m(2) per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease. CONCLUSIONS. This study suggests that while relatively nontoxic at a dose of 3 g/m(2) per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.
PMID: 15309507 [PubMed - as supplied by publisher]
Cancer Res. 1999 Jan 1;59(1):44-7. Synergistic effects of (--)-epigallocatechin gallate with (--)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9.
Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H.
Saitama Cancer Center Research Institute, Japan .
The study on incorporation of [3H](-)-epigallocatechin gallate (EGCG) into human lung cancer cell line PC-9 indicated that the [3H]EGCG incorporation was significantly enhanced by (-)-epicatechin, an inert tea polyphenol without a galloyl moiety. (-)-Epicatechin enhanced apoptosis, growth inhibition of PC-9 cells, and inhibition of tumor necrosis factor-alpha release from BALB/c-3T3 cells by EGCG and other tea polyphenols with a galloyl moiety in a dose-dependent manner. Moreover, the effects of EGCG on induction of apoptosis were also synergistically enhanced by other cancer-preventive agents, such as sulindac and tamoxifen. This paper reports significant evidence that whole green tea is a more reasonable mixture of tea polyphenols for cancer prevention in humans than EGCG alone and that it is even more effective when it is used in combination with other cancer preventives.
PMID: 9892181 [PubMed - indexed for MEDLINE]
------------------------------------------------------------------------- Mutat Res. 1999 Jul 16;428(1-2):339-44. Green tea and cancer chemoprevention.
Suganuma M, Okabe S, Sueoka N, Sueoka E, Matsuyama S, Imai K, Nakachi K, Fujiki H.
Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun, Saitama 362-0806, Japan .
Worldwide interest in green tea as a cancer preventive agent for humans has increased, because it is non-toxic and it is effective in a wide range of organs. (-)-Epigallocatechin gallate (EGCG) is the main constituent of green tea; the others are (-)-epicatechin gallate, (-)-epigallocatechin and (-)-epicatechin (EC). This paper reports the results of our latest pharmacological and biochemical studies with 3H-EGCG, along with studies on human subjects. The study on bioavailability of 3H-EGCG in mice revealed the wide distribution of radioactivity in multiple organs. Specifically, radioactivity was found in all reported target organs of EGCG and green tea extract (digestive tract, liver, lung, pancreas, mammary gland and skin) as well as other organs (brain, kidney, uterus and ovary or testes) in mice. Recently, we demonstrated that EC enhanced incorporation of 3H-EGCG into human lung cancer cell line PC-9 cells. EC along with another cancer preventive agent sulindac also synergistically enhanced apoptosis in PC-9 cells induced by EGCG. Moreover, a case-control study on breast cancer patients revealed that high daily consumption of green tea was associated with a lower recurrence rate among Stages I and II patients. All the results suggest that consumption of green tea is a practical and effective cancer preventive both before cancer onset and after cancer treatment.
PMID: 10518005 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- J Cancer Res Clin Oncol. 2001 Jan;127(1):69-72. Combination cancer chemoprevention with green tea extract and sulindac shown in intestinal tumor formation in Min mice.
Suganuma M, Ohkura Y, Okabe S, Fujiki H.
Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun , Japan .
Green tea is the most effective beverage for cancer prevention in humans. Looking at the concept of combination cancer chemoprevention, we previously reported the synergistic effects of (-)-epigallocatechin gallate (EGCG) with sulindac, and the additive effects of EGCG with tamoxifen, on cancer-preventive activity in human lung cancer cell line PC-9. This paper reports confirmation of the synergistic effects of EGCG with sulindac on the inhibition of intestinal tumors in multiple intestinal neoplasia (Min) mice. Treatment with both green tea extract and sulindac significantly reduced the number of tumors from 72.3 +/- 28.3 to 32.0 +/- 18.7 tumors per mouse, a decrease of 44.3%, whereas treatment with green tea extract alone or with sulindac alone reduced it to 56.7 +/- 3.5 and 49.0 +/- 12.7, respectively. The results also indicated that green tea extract inhibited tumor growth in Min mice almost as potently as sulindac itself did. The three treated groups did not show any adenocarcinomas, whereas 10.8% of the control group did. Since cancer-preventive agents like sulindac and tamoxifen are associated with adverse effects, we discuss the possibility of non-toxic, combination cancer chemoprevention with green tea, looking at the goal of truly effective cancer prevention.
PMID: 11206275 [PubMed - indexed for MEDLINE]
---------------------------------------------------------------------- Jpn J Cancer Res. 1997 Jul;88(7):639-43 Mechanisms of growth inhibition of human lung cancer cell line, PC-9, by tea polyphenols.
Okabe S, Suganuma M, Hayashi M, Sueoka E, Komori A, Fujiki H.
Saitama Cancer Center Research Institute.
(-)-Epigallocatechin gallate (EGCG), the main constituent of green tea, and green tea extract show growth inhibition of various cancer cell lines, such as lung, mammary, and stomach. We studied how tea polyphenols induce growth inhibition of cancer cells. Since green tea extract contains various tea polyphenols, such as EGCG, (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC), the inhibitory potential of each tea polyphenol on the growth of a human lung cancer cell line, PC-9 cells, was first examined. EGC and ECG inhibited the growth of PC-9 cells as potently as did EGCG, but EC did not show significant growth inhibition. The mechanism of growth inhibition by EGCG was studied in relation to cell cycle regulation. Flow cytometric analysis revealed that treatment with 50 microM and 100 microM EGCG increased the percentages of cells in the G2-M phase from 13.8% to 15.6% and 24.1%, respectively. The DNA histogram after treatment with 100 microM EGCG was similar to that after treatment with genistein, suggesting that EGCG induces G2-M arrest in PC-9 cells. Moreover, we found by microautoradiography that [3H]EGCG was incorporated into the cytosol, as well as the nuclei. These results provide new insights into the mechanisms of action of EGCG and green tea extract as cancer-preventive agents in humans.
PMID: 9310136 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Mutat Res. 2003 Feb-Mar;523-524:119-25. New TNF-alpha releasing inhibitors as cancer preventive agents from traditional herbal medicine and combination cancer prevention study with EGCG and sulindac or tamoxifen.
Fujiki H, Suganuma M, Kurusu M, Okabe S, Imayoshi Y, Taniguchi S, Yoshida T.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University , Yamashiro-Cho, Tokushima 770-8514, Japan . hfujiki@ph.bunri-u.ac.jp
Herbal medicines are now attracting attention as potential sources of cancer preventive agents. Using inhibition of tumor necrosis factor-alpha (TNF-alpha) release assay, we studied Acer nikoense, Megusurino-ki in Japanese. Inhibitory potential was found in the leaf extract, and the main active principles were identified as geraniin and corilagin. The IC(50) values for TNF-alpha release inhibition were 43 microM for geraniin and 76 microM for corilagin, whereas that for (-)-epigallocatechin gallate (EGCG), the green tea polyphenol, as control was 26 microM. Furthermore, treatment with geraniin inhibited okadaic acid tumor promotion in a two-stage carcinogenesis experiment on mouse skin. Geraniin and corilagin are present in another well-known Japanese traditional herb, Geranium thunbergii, Genno-shoko in Japanese. Considering seasonal variations of the agents and sites of cultivation of herbs, this paper reviews the significance of geraniin as a new cancer preventive agent. In addition, based on accumulated results of green tea as a cancer preventive, we review two important results with EGCG: the synergistic effects of EGCG with sulindac or tamoxifen on cancer preventive activity in PC-9 cells, and cancer prevention of intestinal tumor development in multiple intestinal neoplasia (Min) mice by cotreatment using EGCG with sulindac. We report here new findings on additional gene expression resulting from cotreatment with EGCG and sulindac in PC-9 cells compared with gene expression by EGCG alone or sulindac alone. Overall, our results indicate that, with the continuing spread of cancer chemoprevention as a fundamental medical strategy, both clinicians and researchers should take a closer look at herbal medicine. Copyright 2002 Elsevier Science B.V.
PMID: 12628509 [PubMed - indexed for MEDLINE]
Carcinogenesis. 1998 Apr;19(4):611-6. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.
Yang GY, Liao J, Kim K, Yurkow EJ, Yang CS.
Laboratory for Cancer Research, College of Pharmacy , Rutgers University , Piscataway , NJ 08855-0789 , USA .
In order to study the biological activities of tea preparations and purified tea polyphenols, their growth inhibitory effects were investigated using four human cancer cell lines. Growth inhibition was measured by [3H]thymidine incorporation after 48 h of treatment. The green tea catechins (-)-epigallocatechin-3-gallate (EGCG) and (-)-epigallocatechin (EGC) displayed strong growth inhibitory effects against lung tumor cell lines H661 and H1299, with estimated IC50 values of 22 microM, but were less effective against lung cancer cell line H441 and colon cancer cell line HT-29 with IC50 values 2- to 3-fold higher. (-)-Epicatechin-3-gallate, had lower activities, and (-)-epicatechin was even less effective. Preparations of green tea polyphenols and theaflavins had higher activities than extracts of green tea and decaffeinated green tea. The results suggest that the growth inhibitory activity of tea extracts is caused by the activities of different tea polyphenols. Exposure of H661 cells to 30 microM EGCG, EGC or theaflavins for 24 h led to the induction of apoptosis as determined by an annexin V apoptosis assay, showing apoptosis indices of 23, 26 and 8%, respectively; with 100 microM of these compounds, the apoptosis indices were 82, 76 and 78%, respectively. Incubation of H661 cells with EGCG also induced a dose-dependent formation of H2O2. Addition of H2O2 to H661 cells caused apoptosis in a manner similar to that caused by EGCG. The EGCG-induced apoptosis in H661 cells was completely inhibited by exogenously added catalase (50 units/ml). These results suggest that tea polyphenol-induced production of H2O2 may mediate apoptosis and that this may contribute to the growth inhibitory activities of tea polyphenols in vitro.
PMID: 9600345 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Mutat Res. 1998 Jun 18;402(1-2):307-10. Cancer inhibition by green tea.
Fujiki H, Suganuma M, Okabe S, Sueoka N, Komori A, Sueoka E, Kozu T, Tada Y, Suga K, Imai K, Nakachi K.
Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun, Saitama 362, Japan .
Green tea is now an acknowledged cancer preventive in Japan . This paper discusses several important features of (-)-epigallocatechin gallate (EGCG), the main constituent of green tea and tea polyphenols. EGCG and other tea polyphenols inhibited growth of human lung cancer cell line, PC-9 cells with G2/M arrest. 3H-EGCG administered by p.o. intubation into mouse stomach revealed that small amounts of 3H-activity were found in various organs where EGCG and green tea extract had previously demonstrated their anticarcinogenic effects, such as skin, stomach, duodenum, colon, liver, lung and pancreas. Cancer onset of patients who had consumed over 10 cups of green tea per day was 8.7 years later among females and 3.0 years later among males, compared with patients who had consumed under three cups per day. The mechanisms of action of EGCG were briefly discussed with regard to inhibition of tumor necrosis factor-alpha (TNF-alpha) release. Copyright 1998 Elsevier Science B. V. All rights reserved.
PMID: 9675322 [PubMed - indexed for MEDLINE]
Jpn J Cancer Res. 1999 Jul;90(7):733-9. Mechanistic aspects of green tea as a cancer preventive: effect of components on human stomach cancer cell lines.
Okabe S, Ochiai Y, Aida M, Park K, Kim SJ, Nomura T, Suganuma M, Fujiki H.
Saitama Cancer Center Research Institute.
It is now well accepted that (-)-epigallocatechin gallate (EGCG) inhibits carcinogenesis in the digestive tract in rodents. To understand the mechanisms of anticarcinogenesis, we first studied growth inhibition by EGCG in human stomach cancer cell lines established at Seoul National University (SNU cell lines). Inhibition by EGCG of [3H]thymidine incorporation into eight SNU cell lines was examined, in relation to transforming growth factor-beta (TGF-beta) responsiveness. Various tea polyphenols derived from green tea and black tea induced growth inhibition and apoptosis of human stomach cancer cell line KATO III, and inhibition of tumor necrosis factor-alpha (TNF-alpha) release from the cells, in the order of (-)-epicatechin gallate (ECG), EGCG, (-)-epigallocatechin (EGC), teaflavins (TF) and (-)-epicatechin (EC). In addition, we demonstrated that EGCG inhibited TNF-alpha gene expression in KATO III cells, as well as okadaic acid-induced AP-1 and NF-kappa B activation. The inhibitory potencies of EGCG for AP-1 and NF-kappa B binding to DNA were different between KATO III cells and mouse fibroblast cell line BALB/3T3. Thus, EGCG and other tea polyphenols may interact with various transcription factors, in addition to AP-1 and NF-kappa B, in nuclei of various cells, resulting in inhibition of TNF-alpha gene expression and TNF-alpha release.
PMID: 10470285 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Biofactors. 2000;13(1-4):67-72. Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF-alpha expression.
Suganuma M, Sueoka E, Sueoka N, Okabe S, Fujiki H.
Saitama Cancer Center Research Institute, Japan .
Among various biochemical and biological activities of tea polyphenols, we believe inhibition of the expression and release of tumor necrosis factor-alpha (TNF-alpha) is crucial, since our study with TNF-alpha-deficient mice has revealed that TNF-alpha is an essential factor in tumor promotion. We found that EGCG dose-dependently inhibited AP-1 and NF-kappaB activation in BALB/3T3 cells treated with okadaic acid, resulting in inhibition of TNF-alpha gene expression. Furthermore, treatment with 0.1% green tea extract in drinking water reduced TNF-alpha gene expression as well as TNF-alpha protein level in the lung of TNF-alpha transgenic mice; and IL-1beta and IL-10 gene expression in the lung was also inhibited by treatment with green tea extract, indicating that green tea inhibits both TNF-alpha and the cytokines induced by TNF-alpha in organs. We recently found synergistic effects of EGCG and cancer preventive agents such as tamoxifen and sulindac, on cancer preventive activity. Taken together, the results show that green tea is efficacious as a non-toxic cancer preventive for humans.
PMID: 11237202 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Life Sci. 2001 Jan 26;68(10):1207-14. Induction of apoptosis by green tea catechins in human prostate cancer DU145 cells.
Chung LY, Cheung TC, Kong SK, Fung KP, Choy YM, Chan ZY, Kwok TT.
Department of Biochemistry, The Chinese University of Hong Kong , Shatin.
Green tea catechins (GTCs) including (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG) and (-)-epicatechin (EC) were shown to suppress cell growth and induce apoptosis in various cell systems in addition to their chemo-preventive effect. In this study, except EC which was inactive, green tea extract (TE) and other 3 GTCs were found to suppress the growth and induce apoptosis in human prostate cancer DU145 cells largely through an increase in reactive oxygen species formation and mitochondrial depolarization. The conclusion was supported by the fact that the profiles for different GTCs in growth suppression, apoptosis induction, ROS formation and mitochondrial depolarization are in a similar order, i.e. ECG > EGCG > EGC > EC. Although the molecular mechanisms are still not clear, apoptosis induced by GTCs is not related to the members of BCL-2 family as EGCG did not alter the expression of BCL-2, BCL-X(L) and BAD in DU145 cells.
PMID: 11228105 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Cancer Lett. 2002 Mar 8;177(1):49-56. Synergistic effects of (-)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane.
Ohishi T, Kishimoto Y, Miura N, Shiota G, Kohri T, Hara Y, Hasegawa J, Isemura M.
School of Food and Nutritional Sciences, University of Shizuoka , 52-1 Yada, Shizuoka 422-8526, Japan .
(-)-Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to exhibit anti-cancer activity. Sulindac is also well known as a cancer-preventive agent against colon cancer, but its usage is restricted because of its adverse effects, as exemplified by gastrointestinal bleeding. In the present study, we examined whether a combination of EGCG and sulindac shows synergistic effects for cancer-preventive activity for rat colon carcinogenesis induced by azoxymethane (AOM); we examined the number of aberrant crypt foci (ACF) representing preneoplastic lesions, the argyrophilic nucleolar organizer region (AgNOR) as an indicator of cell proliferation, and the incidence of apoptosis. The AOM treatment induced an average of 46.2+/-4.9 ACF/colon, and sulindac and EGCG significantly reduced the incidence of ACF/colon to 21.4+/-3.4 and 19.5+/-5.8, respectively (P<0.01). The co-treatment with EGCG and sulindac resulted in significantly reduced ACF formation (10.0+/-3.2; P<0.01). The results of the AgNOR analysis indicated that the treatment with EGCG and/or sulindac suppressed AOM-induced cell proliferation. The present results also revealed that the combination of EGCG and sulindac synergistically enhanced apoptosis significantly (P<0.01). Thus, our findings suggest that EGCG with sulindac synergistically suppresses ACF formation by enhancing apoptosis and, therefore, that EGCG is a suitable candidate for use in combination with cancer-preventive agents, such as sulindac, to reduce their adverse effects.
PMID: 11809530 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Int J Oncol. 2002 Jun;20(6):1233-9 Lung cancer prevention with (-)-epigallocatechin gallate using monitoring by heterogeneous nuclear ribonucleoprotein B1.
Fujimoto N, Sueoka N, Sueoka E, Okabe S, Suganuma M, Harada M, Fujiki H.
Saitama Cancer Center , Ina, Kitaadachi-gun 362-0806, Japan .
Considering the problems involved in prevention of human lung cancer, growth inhibition of human lung cancer cell line A549 was studied with emphasis on two parameters: green tea polyphenols, such as (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG); and heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), a new biomarker of human lung cancer which is highly expressed in the very early stages of human lung cancer. The inhibitory potencies of green tea polyphenols were compared with those of genistein as a control. EGCG or ECG and genistein as a control dose-dependently inhibited the growth of A549 cells, which strongly elevated hnRNP B1 protein, and increased G2/M phase cells associated with induction of apoptotic cells. The results were confirmed by previous evidence with human lung cancer cell line PC-9. Some larger differences in mechanisms of action between green tea polyphenols and genistein were presented. Treatment of A549 cells with EGCG, ECG or genistein significantly inhibited the expression levels of hnRNP B1 mRNA and the elevated levels of hnRNP B1 protein, both of which are constitutively elevated in cancer cells. Furthermore, both EGCG and genistein inhibited the promoter activity of hnRNP A2/B1 gene expression, with IC50 values 29 microM for EGCG and 66 microM for genistein, suggesting the interaction of EGCG or genistein with the transcriptional complex. Looking at our results here, and those of previously reported epidemiological studies with green tea, we discuss the steadily accumulating evidence that clinical trials with green tea extract would be an efficient means of lung cancer prevention.
PMID: 12012004 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Mutat Res. 2001 Sep 1;480-481:299-304 Cancer prevention with green tea and monitoring by a new biomarker, hnRNP B1.
Fujiki H, Suganuma M, Okabe S, Sueoka E, Sueoka N, Fujimoto N, Goto Y, Matsuyama S, Imai K, Nakachi K.
Saitama Cancer Center , Ina, Kitaadachi-gun, Saitama 362-0806, Japan . hfujiki@cancer-c.pref.saitama.jp
The study of green tea polyphenols as a cancer preventative is approaching a new era, with significant results accumulating rapidly. This paper briefly reviews four topics related to mechanisms of action of tea polyphenols: (I) identification of the genes commonly affected by EGCG, as demonstrated by Clontech's Atlas cDNA Expression Array; (II) the significance of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) as a new biomarker for early detection of lung cancer, and inhibition of its expression by EGCG; (III) the synergistic or additive effects of EGCG with the cancer preventive agents, sulindac and tamoxifen, on induction of apoptosis in PC-9 cells and on inhibition of intestinal tumor development in multiple intestinal neoplasia (Min) mice; (IV) the results of a 10 year prospective cohort study demonstrating the effectiveness of daily consumption of green tea in preventing cancer, and a prototype study for developing green tea beverage as cancer preventive.
Publication Types: Review Review, Academic
PMID: 11506822 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Mutat Res. 2003 Feb-Mar;523-524:33-41. Anticlastogenic, antigenotoxic and apoptotic activity of epigallocatechin gallate: a green tea polyphenol.
Roy M, Chakrabarty S, Sinha D, Bhattacharya RK, Siddiqi M.
Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37 SP Mukherjee Road , Kolkata 700 026, India .
Modulation of events characteristic of carcinogenesis or of cancer cells is being emphasized as a rational strategy to control cancer. Green tea polyphenol epigallocatechin gallate (EGCG) has been shown to be highly active as a cancer chemopreventive agent. Certain cellular and molecular events relevant to carcinogenesis are also modified by EGCG. The present investigation was carried out to examine the effects of EGCG on the cytogenetic change and DNA damage induced by toxicant H(2)O(2) and carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Chinese hamster V-79 cells in culture. Cytogenetic change as evident by the formation of micronuclei and DNA damage in the form of comet tail length during single cell gel electrophoresis was found to be significantly suppressed by EGCG in a dose dependent manner. Cells preincubated with EGCG were protected from subsequent damage by the genotoxic agents. Apoptosis, a highly organized physiological mechanism to eliminate injured or abnormal cells, is also implicated in multistage carcinogenesis. Initiated cells, cells at promotional stage or fully transformed cells can be eliminated through apoptosis. It was observed that EGCG suppressed growth and proliferation of K-562 cells derived from human chronic myelogenic leukemia. Morphological features of treated cells and characteristic DNA fragmentation revealed that the cytotoxicity was due to induction of apoptosis. This was mediated by activation of caspase 3 and caspase 8. Results show that EGCG not only protects normal cells against genotoxic hazard but also eliminate cancer cells through induction of apoptosis. Copyright 2002 Elsevier Science B.V.
PMID: 12628501 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
Amino Acids. 2002;22(2):131-43. The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG).
Wang YC, Bachrach U.
Department of Molecular Biology, Hebrew University-Hadassah Medical School , Jerusalem , Israel .
The effect of the green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG) was tested in cultures of normal and transformed NIH-pATM ras fibroblasts. In this system transformation can be induced at will by the addition of dexamethasone, which induces the expression of H- ras by activating the mammary tumor virus long terminal repeat (MMTV-LTR) promoter. This facilitates a reliable comparison of the susceptibility of normal and transformed cells to EGCG. It has been shown that EGCG inhibited the growth of transformed but not of the normal fibroblasts. In an attempt to elucidate the mode of the preferential inhibitory activity of EGCG, its effect on growth promoting factors has been examined. The level of ornithine decarboxylase (ODC, EC 4.1.1.17), which is a signal for cellular proliferation, was reduced by EGCG in the transformed but not in the normal cells. EGCG also showed strong inhibition of tyrosine kinase and mitogen-activated protein kinase (MAPK) activities, without affecting the kinases in the normal cells. Similarly, EGCG also preferentially decreased the levels of the oncogenes Ras and Jun in transformed cell. EGCG preferentially induced apoptosis in the transformed fibroblasts. In vitro chemosensitivity tests demonstrated that EGCG inhibited the proliferation of leukemic cells. These findings suggest that EGCG has a therapeutic potential in the combat against cancer.
PMID: 12395181 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- J Natl Cancer Inst. 1997 Dec 17;89(24):1881-6. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells.
Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H.
Department of Dermatology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
BACKGROUND AND PURPOSE: The polyphenolic compounds present in green tea show cancer chemopreventive effects in many animal tumor models. Epidemiologic studies have also suggested that green tea consumption might be effective in the prevention of certain human cancers. We investigated the effect of green tea polyphenols and the major constituent, epigallocatechin-3-gallate, on the induction of apoptosis (programmed cell death) and regulation of cell cycle in human and mouse carcinoma cells. METHODS: Human epidermoid carcinoma cells (cell line A431), human carcinoma keratinocyte (cell line HaCaT), human prostate carcinoma cells (cell line DU145), mouse lymphoma cells (cell line L5178Y), and normal human epidermal keratinocytes (NHEKs) were used. Apoptosis was assessed by 1) the formation of internucleosomal DNA fragments by agarose gel electrophoresis, 2) confocal microscopy, and 3) flow cytometry after tagging the DNA fragments by fluorescence label. The distribution of cells in different phases of the cell cycle was analyzed by flow cytometry. RESULTS: Treatment of A431 cells with green tea polyphenols and its components, epigallocatechin-3-gallate, epigallocatechin, and epicatechin-3-gallate, resulted in the formation of internucleosomal DNA fragments, characteristic of apoptosis. Treatment with epigallocatechin-3-gallate also resulted in apoptosis in HaCaT, L5178Y, and DU145 cells, but not in NHEK. Confocal microscopy and flow cytometry confirmed the findings. The DNA cell cycle analysis showed that in A431 cells, epigallocatechin-3-gallate treatment resulted in arrest in the G0-G1 phase of the cell cycle and a dose-dependent apoptosis. CONCLUSIONS: Green tea may protect against cancer by causing cell cycle arrest and inducing apoptosis. It needs to be evaluated in human trials.
PMID: 9414176 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Oncol Rep. 1998 Mar-Apr;5(2):527-9 Induction of apoptosis in human stomach cancer cells by green tea catechins.
Hibasami H, Komiya T, Achiwa Y, Ohnishi K, Kojima T, Nakanishi K, Akashi K, Hara Y.
Faculty of Medicine, Mie University , Tsu-city, Mie 514, Japan .
The exposure of human stomach cancer KATO III cells to green tea catechin extract and epigallocatechin gallate (EGCG), a main component of the extract led to both growth inhibition and the induction of programmed cell death (apoptosis). Morphological changes showing apoptotic body were observed in the cells treated with green tea catechin extract and EGCG. The fragmentation of DNA to oligonucleosomal-sized fragments, characteristic of apoptosis was determined to be concentration- and time-dependent. These data suggest that drinking of green tea in large amounts is recommended possibly to protect humans from stomach cancer.
PMID: 9468594 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Life Sci. 1998;63(16):1397-403 Growth inhibition of leukemic cells by (-)-epigallocatechin gallate, the main constituent of green tea.
Otsuka T, Ogo T, Eto T, Asano Y, Suganuma M, Niho Y.
First Department of Internal Medicine, Faculty of Medicine, Kyushu University , Fukuoka , Japan .
In this report, we presented the results that EGCG, the main constituent of the polyphenols present in Japanese green tea inhibited growth of leukemic cell lines of both human and mice. The proliferation of human leukemic cell lines and mouse NFS60 cell line was inhibited by EGCG. Sensitivity of each line to EGCG was different, and more than 50% of DNA synthesis was reduced in all the cell lines in the presence of 50 microM EGCG. On the other hand, normal hematopoietic progenitor cells retained their natural function of supplying mature cells of various lineages in the presence of less than 10 microM EGCG in vitro. Even in the presence of 100 microM EGCG, half the colonies containing all the lineages of cells were developed. All the dead cells of each line showed characteristics of apoptosis, which might be due to inhibition by EGCG of growth factors' signaling. Besides anticarcinogenic activity, EGCG is expected to have a new function for leukemia therapy without side effects.
PMID: 9952285 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------- Cancer Lett. 1998 Aug 14;130(1-2):1-7 Induction of apoptosis in prostate cancer cell lines by the green tea component, (-)-epigallocatechin-3-gallate.
Paschka AG, Butler R, Young CY.
Department of Urology, Mayo Clinic/Foundation, Rochester , MN 55905 , USA .
Green tea components exert many biological effects, including antitumor and cancer preventive activities. In the search for anticancer agents for prostate cancer the inhibitory effects of green tea components were tested on the prostate cancer cell lines LNCaP, PC-3 and DU145. (-)-Epigallocatechin-3-gallate (EGCG) proved to be the most potent catechin at inhibiting cell growth. The inhibition induced by EGCG was found to occur via apoptotic cell death as shown by changes in nuclear morphology and DNA fragmentation. Thus, we report the first evidence that EGCG is the active component in green tea and induces apoptosis in human prostate cancer cells.
PMID: 9751250 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Jpn J Clin Oncol. 1993 Jun;23(3):186-90. Anticarcinogenic activity of green tea polyphenols.
Komori A, Yatsunami J, Okabe S, Abe S, Hara K, Suganuma M, Kim SJ, Fujiki H.
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo .
The main physiologically active polyphenol in green tea extract is (-)-epigallocatechin gallate (EGCG). Green tea extract has an advantage over EGCG as a cancer chemopreventive agent for humans, as is apparent from the Japanese custom of injesting green tea on a daily basis. Green tea extract similarly inhibited protein kinase C activation by teleocidin, a tumor promoter, as did EGCG. In addition, EGCG and green tea extract showed inhibitory effects on the growth of lung and mammary cancer cell lines with similar potencies. An experiment using the estrogen-dependent MCF-7 cell line showed the mechanisms of action of these compounds to be inhibiting the interaction of estrogen with its receptors. Considering our previous results of a single application of EGCG to mouse skin inhibiting the specific binding of 3H-12-0-tetradecanoylphorbol-13-acetate (3H-TPA) and 3H-okadaic acid, we postulated that EGCG and compounds in green tea extracts would block the interaction of tumor promoters, hormones and growth factors with their receptors: a kind of sealing effect. The sealing effect would account for reversible growth arrest, and may be induced by various kinds of compound.
PMID: 8350491 [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.
Publication Types: Review Review, Tutorial
PMID: 10757128 [PubMed - indexed for MEDLINE]
Gynecol Oncol. 2004 Jan;92(1):197-204. The tea polyphenol, (-)-epigallocatechin gallate effects on growth, apoptosis, and telomerase activity in cervical cell lines.
Yokoyama M, Noguchi M, Nakao Y, Pater A, Iwasaka T.
Department of Obstetrics and Gynecology, Saga Medical School , Saga , Japan . yokoyam1@post.saga-med.ac.jp
OBJECTIVE: To investigate the effect of the major tea polyphenol, (-)-epigallocatechin gallate (EGCG) in cervical carcinogenesis. METHODS: Cell growth rate was examined after treatment for 4, 7, and 10 days with 0-100 microM EGCG in primary human endocervical cells (HEN), human papillomavirus type 18 (HPV 18)-immortalized endocervical cell (HEN-18), ectocervical cell (HEC-18), serum-adapted HEN-18 (HEN-18S), transformed HEC-18 (HEN-18T), and four cervical cancer cell lines. The effect of EGCG treatment was examined on dysplastic epithelium formation in organotypic culture, induction of apoptosis by DNA ladder assay and telomerase activity by PCR telomere extension assay. RESULTS: EGCG inhibited growth more than 90% in HEN-18 and HEC-18, whereas growth inhibition was less in ME180, TMCC-1, HeLa, SiHa, HEC-18T, and HEN-18S. In organotypic culture, thickness of epithelial multilayers was decreased in all EGCG-treated cells. EGCG resulted in apoptosis of HEN-18 or HEC-18, but not HEN-18S nor HEC-18T and inhibited telomerase activity in HEN-18 and HEC-18, as well as HEN-18S and HEC-18T. CONCLUSION: Our data suggest that EGCG prevents the carcinogenesis of cervical cancer, induces apoptosis and inhibited telomerase activity. The effect by EGCG treatment may be associated with the induction of apoptosis and telomerase inhibition in early cervical lesions.
PMID: 14751158 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Cancer Lett. 2002 Dec 15;188(1-2):9-13. Green tea: cancer preventive beverage and/or drug.
Fujiki H, Suganuma M, Imai K, Nakachi K.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University , Yamashiro-cho, 770-8514, Tokushima , Japan . hfujiki@ph.bunri-u.ac.jp
Green tea and (-)-epigallocatechin gallate (EGCG) are now acknowledged cancer preventives in Japan and has made it possible for us to establish the concept of a cancer preventive beverage. For the general population, we recommend 10 cups of green tea daily supplemented with green tea tablets. For cancer patients following treatment, we here present new evidence that green tea and a cancer preventive drug, sulindac, have synergistic preventive effects. An approach to develop green tea capsules as a cancer preventive drug in the US is discussed, aiming at taking full advantage of this cancer preventive beverage.
Publication Types: Review Review, Tutorial
PMID: 12406542 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Biofactors. 2000;13(1-4):81-5. Tea catechins and related polyphenols as anti-cancer agents.
Isemura M, Saeki K, Kimura T, Hayakawa S, Minami T, Sazuka M.
Laboratory of Cellular Biochemistry, Graduate School of Nutritional and Environmental Sciences, The University of Shizuoka , Japan .
Epigallocatechin gallate (EGCg) and theaflavins, a major constituent of green tea infusion and the constituents of black tea, respectively, were found to inhibit matrix metalloproteinases (MMPs) which are intimately associated with tumor invasion and metastasis. EGCg and related polyphenols exhibited apoptosis-inducing activity for several cancer cell lines including human stomach and colon cancer cells. Comparison of the activity of these compounds revealed the importance of the number and the steric disposition of hydroxyl groups. A pyrogallol-type structure in a molecule is a minimum requirement for apoptosis induction of catechin compounds and that in the B ring has an important role in the activity. These data would provide useful information for designing anti-cancer agents on the basis of anti-inhibitory activity for MMPs and/or apoptosis-inducing activity.
PMID: 11237204 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Anticancer Res. 1999 Sep-Oct;19(5B):4343-8. Effect of anticancer drugs, metals and antioxidants on cytotoxic activity of epigallocatechin gallate.
Ishino A, Mita S, Watanabe S, Sakagami H.
Department of Dental Pharmacology, Meikai University School of Dentistry, Saitama , Japan .
Various modulation factors for the cytotoxic action of epigallocatechin gallate (EGCG) against two human oral tumor cell lines (HSC-2, HSG) were investigated. Three anticancer drugs (tamoxifen, sulindac, doxorubicin), two metals (CuCl2, FeCl3) and two antioxidants (sodium ascorbate, tiopronin) did not significantly affect the cytotoxic activity of EGCG, Catalase and N-acetyl-L-cysteine only marginally reduced the cytotoxic activity of EGCG. On the other hand, CoCl2 significantly protected the cell injury induced by EGCG. This suggests that the site of EGCG action might be intracellular rather than extracellular. Possible involvement of the expression of transcription factor (s) for EGCG-induced cytotoxicity is discussed.
PMID: 10628398 [PubMed - indexed for MEDLINE] -------------------------------------------------------------------------------------------- Carcinogenesis. 1998 Oct;19(10):1771-6. Wide distribution of [3H](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue.
Suganuma M, Okabe S, Oniyama M, Tada Y, Ito H, Fujiki H.
Saitama Cancer Center Research Institute, Japan . masami@saitama-cc.go.jp
The increasing recognition of green tea and tea polyphenols as cancer preventives has created a need for a study of their bioavailability. For this purpose, we synthesized [3H] (-)-epigallocatechin gallate ([3H]EGCG) with a specific activity of 48.1 GBq/mmol and directly administered the solution into the stomachs of CD-1 female or male mice. Radioactivity in the digestive tract, various organs, blood, urine and feces was measured with an oxidizer at various times after administration and significant radioactivity was found in the previously reported target organs of EGCG and green tea extract (digestive tract, liver, lung, pancreas, mammary gland and skin), as well as other organs (brain, kidney, uterus and ovary and testes) in both sexes. Incorporation of radioactivity in the cells was confirmed by microautoradiography. Within 24 h, 6.6 (females) and 6.4% (males) of total administered radioactivity was excreted in the urine and 37.7 and 33.1% in feces. HPLC analysis of urine from both sexes revealed that 0.03-0.59% of administered [3H]EGCG, along with at least five metabolites, was excreted. In addition, we found that a second, equal administration to female mice after a 6 h interval enhanced tissue levels of radioactivity in blood, brain, liver, pancreas, bladder and bone 4-6 times above those after a single administration. These results suggest that frequent consumption of green tea enables the body to maintain a high level of tea polyphenols and this paper is the first pharmacological evidence of a wide distribution of [3H]EGCG in mouse organs, indicating a similar wide range of target organs for cancer prevention in humans.
PMID: 9806157 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Cancer Lett. 1998 Jul 17;129(2):173-9. Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts.
Chen ZP, Schell JB, Ho CT , Chen KY.
Department of Chemistry, Rutgers , The State University of New Jersey , Piscataway 08855-0939 , USA .
(-)-Epigallocatechin gallate (EGCG), a catechin polyphenol compound, represents the main ingredient of green tea extract. Although EGCG has been shown to be growth inhibitory in a number of tumor cell lines, it is not clear whether the effect is cancer-specific. In this study we compared the effect of EGCG on the growth of SV40 virally transformed WI38 human fibroblasts (WI38VA) with that of normal WI38 cells. The IC50 value of EGCG was estimated to be 120 and 10 microM for WI38 and WI38VA cells, respectively. Thus, EGCG at 40 microM completely inhibited the growth of WI38VA cells, but had little or no inhibitory effect on the growth of WI38 cells. Similar differential growth inhibition was also observed between a human colorectal cancer cell line (Caco-2), a breast cancer cell line (Hs578T) and their respective normal counterparts. EGCG at a concentration range of 40-200 microM induced a significant amount of apoptosis in WI38VA cultures, but not in WI38 cultures, as determined by terminal deoxynucleotidyl transferase assay. After exposure to EGCG at 200 microM for 8 h, more than 50% of WI38VA cells in a confluent culture became apoptotic. In contrast, less than 1% of WI38 cells displayed apoptotic labeling under the same condition. EGCG did not affect the serum-induced expression of c-fos and c-myc genes in normal WI38 cells. However, it significantly enhanced their expression in transformed W138VA cells. It is possible that differential modulation of certain genes, such as c-fos and c-myc, may cause differential effects of EGCG on the growth and death of cancer cells.
PMID: 9719459 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Pharmacol Toxicol. 2003 May;92(5):234-41.
Tea catechin synergies in inhibition of cancer cell proliferation and of a cancer specific cell surface oxidase (ECTO-NOX).
Morre DJ, Morre DM, Sun H, Cooper R, Chang J, Janle EM.
Departments of Medicinal Chemistry and Molecular Pharmacology, Purdue University , West Lafayette , IN 47907 , USA . morre@pharmacy.purdue.edu
The anticancer properties of tea catechins are most frequently attributed to the principal catechin (-)-epigallocatechin-3-gallate (EGCg). Efficacy was evaluated using growth of cultured HeLa cells and inhibition of the enzymatic activity of a putative cell surface tea target enzyme, a cancer-associated cell surface-located NADH oxidase (ECTO-NOX) designated tNOX. The amounts of EGCg required to inhibit by both criteria was reduced 10 times by combination with inactive catechins such as (-)-epicatechin (EC), (-)-epigallocatechin (EGC) or (-)-epicatechin-3-gallate (ECG). Various synthetic mixtures based on purified catechins and decaffeinated tea extracts treated enzymatically to reduce the ester bond-containing catechins varying in EGCg content from 0.065 to 40% were of comparable efficacy to decaffeinated green tea extracts as long as EGCg was present and the ratio of total catechins to EGCg + EGC was about 1.5. Such mixtures appear to offer potential cancer protection and therapeutic advantages over those of EGCg alone through lowered toxicity of the mixture to normal cells and for more efficient blood delivery of orally-administered catechins to a tumour site.
PMID: 12753411 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Prev Med. 1992 Jul;21(4):503-9. Anticarcinogenic effects of (-)-epigallocatechin gallate.
Fujiki H, Yoshizawa S, Horiuchi T, Suganuma M, Yatsunami J, Nishiwaki S, Okabe S, Nishiwaki-Matsushima R, Okuda T, Sugimura T.
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo , Japan .
BACKGROUND. Our research objective is to develop nontoxic cancer chemopreventive agents and to apply these agents in treating humans. We are identifying agents that inhibit the process of tumor promotion in two-stage carcinogenesis experiments on mouse skin. METHODS. We review (a) the inhibitory effect of penta-O-galloyl-beta-D-glucose (5GG) on tumor promotion by teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters (5GG is structurally similar to (-)-epigallocatechin gallate (EGCG) and is isolated from hydrolyzed tannic acid); (b) the inhibitory effects of EGCG, the main constituent of Japanese green tea, on tumor promotion with two tumor promoters, teleocidin and okadaic acid, a non-TPA-type tumor promoter; (c) the mechanisms of action of EGCG, a single application of which reduced the specific binding of [3H]TPA and [3H]okadaic acid to a particulate fraction of mouse skin; and (d) the anticarcinogenic effects of EGCG on duodenal carcinogenesis induced by N-ethyl-N'-nitro-N-nitrosoguanidine in male C57BL/6 mice. EGCG is a nontoxic compound. CONCLUSION. We believe that the main constituent of Japanese green tea, EGCG, is a practical cancer chemopreventive agent available in everyday life.
Publication Types: Review Review, Tutorial
PMID: 1409491 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Carcinogenesis. 1998 Dec;19(12):2201-4. (-)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1 activity.
Barthelman M, Bair WB 3rd, Stickland KK, Chen W, Timmermann BN, Valcic S, Dong Z, Bowden GT.
Department of Radiation Oncology, University of Arizona Health Sciences Center , Tucson 85724 , USA .
Green tea polyphenols have been shown to inhibit cancer in a variety of tumor models, including ultraviolet B (UVB)-induced non-melanoma skin cancer. In green tea extracts, the major dry mass constituent is the family of catechins, of which (-)-epigallocatechin-(3)-gallate (EGCG) is considered to be important for the chemopreventive activity. EGCG has been shown to have antioxidant properties, but there has been little progress toward identifying the specific targets and mechanisms of its action. Using cultured human keratinocytes, we show that UVB-induced AP-1 activity is inhibited by EGCG in a dose range of 5.45 nM to 54.5 microM. EGCG is effective at inhibiting AP-1 activity when applied before, after or both before and after UVB irradiation. EGCG also inhibits AP-1 activity in the epidermis of a transgenic mouse model. This work begins to define a mechanism by which EGCG could be acting to inhibit UVB-induced tumor formation.
PMID: 9886579 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Biochem Biophys Res Commun. 2000 Aug 28;275(2):328-34. Cell cycle dysregulation by green tea polyphenol epigallocatechin-3-gallate.
Ahmad N, Cheng P, Mukhtar H.
Department of Dermatology, Case Western Reserve University , 11100 Euclid Avenue, Cleveland , Ohio 44106 , USA .
Epidemiological, in vitro cell culture, and in vivo animal studies have shown that green tea or its constituent polyphenols, particularly its major polyphenol epigallocatechin-3-gallate (EGCG) may protect against many cancer types. In earlier studies, we showed that green tea polyphenol EGCG causes a G0/G1-phase cell cycle arrest and apoptosis of human epidermoid carcinoma (A431) cells. We also demonstrated that these effects of EGCG may be mediated through the inhibition of nuclear factor kappa B that has been associated with cell cycle regulation and cancer. In this study, employing A431 cells, we provide evidence for the involvement of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery during cell cycle deregulation by EGCG. As shown by immunoblot analysis, EGCG treatment of the cells resulted in significant dose- and time-dependent (i) upregulation of the protein expression of WAF1/p21, KIP1/p27, p16 and p18, (ii) downmodulation of the protein expression of cyclin D1, cdk4 and cdk6, but not of cyclin E and cdk2, (iii) inhibition of the kinase activities associated with cyclin E, cyclin D1, cdk2, cdk4 and cdk6. Taken together, our study suggests that EGCG causes an induction of G1-phase ckis, which inhibit the cyclin-cdk complexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-phase arrest of the cell cycle, which is an irreversible process ultimately resulting in an apoptotic cell death. We suggest that the naturally occurring agents such as green tea polyphenols which may inhibit cell cycle progression could be developed as potent anticancer agents for the management of cancer. Copyright 2000 Academic Press.
PMID: 10964666 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Int J Mol Med. 2002 Sep;10(3):311-5.
Prevention of carcinogenesis of mouse mammary epithelial cells RIII/MG by epigallocatechin gallate.
Yanaga H, Fujii T, Koga T, Araki R, Shirouzu K.
Department of Surgery, School of Medicine , Kurume University , Asahimachi Kurume, Fukuoka 830-0011, Japan .
The chemopreventive effect of the polyphenols abundant in green tea on carcinogenesis has been attracting attention in recent years. Among tea polyphenols, epigallocatechin gallate (EGCG) has been studied as a preventive substance for carcinogenesis. We investigated the chemopreventive effect in a group treated with EGCG in vitro and in vivo using mouse mammary epithelial cells RIII/MG. In the in vitro experiment, crude catechin (catechin) containing 50% or more EGCG significantly inhibited the growth of RIII/MG cells, which were precancerous cultured cells. Many cells died, and a DNA ladder was observed. In the in vivo experiment, RIII/MG cells formed a tumor after 13 weeks in a group without catechin treatment, and the tumor formation rate in the 20th week was 40%. In a group treated with 0.1% catechin, a tumor began to grow in the 13th week, and the tumor formation rate in the 20th week was 20%. In a group treated with 1% catechin, no tumor was detected even in the 20th week. There was no significant difference in the change in body weight between the catechin treatment groups and the non-treatment group during the observation period. Tissue samples were stained by the nick-end-labeling method and apoptosis was observed in many cells. Based on the above findings, EGCG inhibited growth in the mouse viral mammary epithelial carcinogenesis model RIII/MG, and induced apoptosis, suggesting a clinical usefulness of EGCG as a chemopreventive substance.
PMID: 12165806 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Bull Cancer. 1999 Sep;86(9):721-4. [Multiple actions of EGCG, the main component of green tea]
[Article in French]
L'Allemain G.
Centre de biochimie CNRS/Inserm, Universite de Nice Sophia-Antipolis, Parc Valrose , 06108 Nice Cedex 2.
Green tea, the most popular beverage in Japan and China , contains epicatechin-derived compounds which have been characterized in some epidemiological studies as having protective effects against cancer. Epigallo catechin-O-gallate (EGCG), the most active epicatechin in green tea was previously found to block the in vitro growth of many cancer cell lines and in vivo to strongly reduce tumor growth in cancer-bearing animals. Today, green tea consumption by animals is shown to markedly reduce VEGF-induced angiogenesis, a neo-vascularization process occurring in several physio-pathological conditions. EGCG is also able to inhibit endothelial cell growth in vitro and angiogenesis process in vivo. Elsewhere, EGCG has been described as a potent inducer of apoptosis and an inhibitor of telomerase activity. Because EGCG is acting on different processes, it could trigger various molecular mechanisms of action. Its anti-oxidant properties could explain its antagonistic action in some inflammatory processes. In summary, although no direct molecular target has been so far elucidated for EGCG, the multi-potentialities of this molecule, along with its broad bioavailability, render it very attractive as a putative curative drug for various diseases such as dermatosis, gout, atherosclerosis and cancer.
PMID: 10519963 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Cancer Res. 1999 Sep 15;59(18):4610-7.
Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved.
Chung JY, Huang C, Meng X, Dong Z, Yang CS.
Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USA.
ras gene mutation, which perpetually turns on the growth signal transduction pathway, occurs frequently in many cancer types. The mouse epidermal JB6 cell line has been transfected with a mutant H-ras gene to mimic carcinogenesis in vitro. These transformed cells (30.7b Ras 12) are able to grow in soft agar, exhibiting anchorage independence and high endogenous activator protein 1 (AP-1) activity, which can be detected by a stable AP-1 luciferase reporter. The present study investigated the ability of different pure green and black tea polyphenols to inhibit this ras signaling pathway. The major green tea polyphenols (catechins), (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin-3-gallate, (-)-epicatechin, and their epimers, and black tea polyphenols, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate (TFdiG), were compared with respect to their ability to inhibit the growth of 30.7b Ras 12 cells and AP-1 activity. All of the tea polyphenols except (-)-epicatechin showed strong inhibition of cell growth and AP-1 activity. Among the catechins, both the galloyl structure on the B ring and the gallate moiety contributed to the growth inhibition and AP-1 activity; the galloyl structure appeared to have a stronger effect on the inhibitory action than the gallate moiety. The epimers of the catechins showed similar inhibitory effects on AP-1 activity. The addition of catalase to the incubation of the cells with EGCG or TFdiG did not prevent the inhibitory effect on AP-1 activity, suggesting that H2O2 does not play a significant role in the inhibition by tea polyphenols. Both EGCG and TFdiG inhibited the phosphorylation of p44/42 (extracellular signal-regulated kinase 1 and 2) and c-jun without affecting the levels of phosphorylated-c-jun-NH2-terminal kinase. TFdiG inhibited the phosphorylation of p38, but EGCG did not. EGCG lowered the level of c-jun, whereas TFdiG decreased the level of fra-1. These results suggest that tea polyphenols inhibited AP-1 activity and the mitogen-activated protein kinase pathway, which contributed to the growth inhibition; however, different mechanisms may be involved in the inhibition by catechins and theaflavins.
PMID: 10493515 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
Proc Soc Exp Biol Med. 1999 Apr;220(4):225-8.
Mechanistic findings of green tea as cancer preventive for humans.
Fujiki H, Suganuma M, Okabe S, Sueoka E, Suga K, Imai K, Nakachi K, Kimura S.
Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun, Saitama 362-0806, Japan . hfuji@saitama-cc.go.jp
Based on our initial work with green tea, in which repeated topical applications of (-)-epigallocatechin gallate (EGCG), the main green tea polyphenol, inhibited tumor promotion in a two-stage carcinogenesis experiment on mouse skin (Phytother Res 1, 44-47, 1987), numerous scientists have since provided so much additional evidence of the benefits of drinking green tea that it is now an acknowledged cancer preventive in Japan, and will possibly soon be recognized as such in other countries. Our work has so far produced several important results with EGCG and green tea: a wide range of target organs in animal experiments for cancer prevention, wide bioavailability of 3H-EGCG in various organs of mice, delayed cancer onset of patients with a history of consuming over 10 cups of green tea per day, and absence of any severe adverse effects among volunteers who took 15 green tea tablets per day (2.25 g green tea extracts, 337.5 mg EGCG, and 135 mg caffeine) for 6 months. This paper introduces three new findings: 1) EGCG interacted with the phospholipid bilayer membrane resulting in confirmation of the sealing effect of EGCG; 2) EGCG inhibited TNF-alpha gene expression in the cells and TNF-alpha release from the cells; 3) high consumption of green tea was closely associated with decreased numbers of axillary lymph node metastases among premenopausal Stage I and II breast cancer patients, and with increased expression of progesterone and estrogen receptors among postmenopausal ones. These results provide new insights into our understanding of the mechanisms of action of tea polyphenols and green tea extract as a cancer preventive.
Publication Types: Review Review, Tutorial
PMID: 10202393 [PubMed - indexed for MEDLINE]
------------------------------------------------------------------------------------- Anticancer Res. 2000 Sep- Oct;20(5B):3459-65.
Effect of tea polyphenols on growth of oral squamous carcinoma cells in vitro.
Elattar TM, Virji AS.
Hormone Research Laboratory, University of Missouri-Kansas City, School of Dentistry and Medicine, Kansas City, MO 64108, USA.
Epidemiologic evidence indicates that both black and green tea is a rich source of flavonoids and other polyphenolic antioxidants which protects against heart disease and cancer. In the current investigation, utilizing human oral squamous carcinoma cell line SCC-25, we have evaluated the effect of three major tea constituents, (-)-epigallocatechin-3-gallate (EGCG), (-)-epicatechin-3-gallate (ECG) and (-)-epigallocatechin (EGC) on cell growth and DNA synthesis. Test agents in concentrations of 50, 80, 100 and 200 microM were incubated in triplicates in DMEM-HAM's F-12 (50: 50) supplemented with 10% calf serum and antibiotics in an atmosphere of 5% CO2 in air for 72 hrs. Cell growth was determined by alamarBlue assay method and DNA synthesis was measured by the incorporation of [3H]-thymidine in nuclear DNA. At the four dose levels used, the three compounds induced significant dose-dependent inhibition in cell growth. In DNA study, the three compounds exhibited stimulatory effect at 50 microM followed by significant dose-dependent inhibitory effect (10 to 100%) at 80, 100 and 200 microM dose levels. Dose-dependent changes in cell morphology were also observed with phase-contrast microscopy after cell treatment with EGCG.
PMID: 11131648 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Redox Rep. 2002;7(3):171-7.
Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells.
Nie G, Cao Y, Zhao B.
Laboratory of Visual Information Processing, Department of Molecular and Cell Biophysics, Institute of Biophysics, Academia Sinica, 15 Datun Road , Chaoyang District, Beijing 100101, P.R. China.
Green tea polyphenols exert a wide range of biochemical and pharmacological effects, and have been shown to possess antimutagenic and anticarcinogenic properties. Oxidative stress is involved in the pathogenesis of Parkinson's disease. However, although green tea polyphenols may be expected to inhibit the progression of Parkinson's disease on the basis of their known antioxidant activity, this has not previously been established. In the present study, we evaluated the neuroprotective effects of green tea polyphenols in the Parkinson's disease pathological cell model. The results show that the natural antioxidants have significant inhibitory effects against apoptosis induced by oxidative stress. 6-Hydroxydopamine (6-OHDA)-induced apoptosis in catecholaminergic PC12 cells was chosen as the in vitro model of Parkinson's disease in our study. Apoptotic characteristics of PC12 cells were assessed by MTT assay, flow cytometry, fluorescence microscopy and DNA fragmentation. Green tea polyphenols and their major component, EGCG at a concentration of 200 microM, exert significant protective effects against 6-OHDA-induced PC12 cell apoptosis. EGCG is more effective than the mixture of green tea polyphenols. The antioxidant function of green tea polyphenols may account for this neuroprotective effect. The present study supports the notion that green tea polyphenols have the potential to be effective as neuropreventive agents for the treatment of neurodegenerative diseases.
PMID: 12189048 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Anticancer Res. 2001 Nov-Dec;21(6A):3743-8.
Chemopreventive effects of green tea polyphenols correlate with reversible induction of p57 expression.
Hsu S, Lewis JB, Borke JL, Singh B, Dickinson DP, Caughman GB, Athar M, Drake L, Aiken AC, Huynh CT, Das BR, Osaki T, Schuster GS.
Department of Oral Biology and Maxillofacial Pathology, School of Dentistry , Medical College of Georgia, Augusta 30912-1126 , USA . shsu@mail.mcg.edu
Green tea polyphenols are known to induce apoptosis in certain types of tumor cells. However, the mechanism(s) that enables normal cells to evade the apoptotic effect is still not understood. In this study, Western blot analysis combined with cycloheximide treatment was used to examine the effects of green tea polyphenols on the expression levels of p57, a cyclin-dependent kinase and apoptosis inhibitor, in normal human keratinocytes and in the oral carcinoma cell lines SCC25 and OSC2. The results showed that the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), induced p57 in normal keratinocytes in a dosage- and time-dependent manner, while the levels of p57 protein in oral carcinoma cells were unaltered. The differential response in p57 induction was consistent with the apoptosis status detected by annexin V assay. The data suggest that the chemopreventive effects of green tea polyphenols may involve p57-mediated cell cycle regulation in normal epithelial cells.
PMID: 11911242 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Cancer. 2001 Feb 15;91(4):822-32.
Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate.
Garbisa S, Sartor L, Biggin S, Salvato B, Benelli R, Albini A.
Department of Experimental Biomedical Sciences, Medical School, University of Padova, viale G. Colombo 3, 35121 Padova, Italy. garbisa@civ.bio.unipd.it
BACKGROUND: Given the association of consumption of green tea with prevention of cancer development, metastasis, and angiogenesis, the effect of the main flavanol present, epigallocatechin-3-gallate (EGCG), on two gelatinases most frequently overexpressed in cancer and angiogenesis (MMP-2 and MMP-9) and on tumor cell invasion and chemotaxis were examined. METHODS: Zymography, Western blotting, and enzyme linked immuoadsorbent assay were used to analyze the effect of EGCG on MMP-2 and MMP-9 activity, whereas its effect on tumor cell invasion and chemotaxis was examined using modified Boyden chamber assays. RESULTS: A Zn2+ chelation-independent, dose-dependent, noncompetitive inhibition by EGCG of both gelatinases was found at concentrations 500 times lower than that reported to inhibit urokinase. Tumor cell invasion of a reconstituted basement membrane matrix, but not chemotaxis, was reduced by 50% with EGCG concentrations equivalent to that in the plasma of moderate green tea drinkers, and 2 orders of magnitude below those of tissue inhibitors of MMPs. Although higher concentrations of EGCG were associated with increased levels of both cell-associated gelatinases and their activator MT1-MMP, no increased gelatinase activation was found, and TIMP-1 and TIMP-2 inhibitors were up-regulated. Finally, concentrations of EGCG active in restraining proliferation and inducing apoptosis of transformed cells were more than 100 times lower than those reported for normal cells. CONCLUSIONS: Epigallocatechin-3-gallate is a potent inhibitor of gelatinases and an orally available pharmacologic agent that may confer the antiangiogenic and antimetastatic activity associated with green tea. Copyright 2001 American Cancer Society.
PMID: 11241252 [PubMed - indexed for MEDLINE]
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J Postgrad Med. 2004 Apr-Jun;50(2):145-9. Vegetables, fruits and phytoestrogens in the prevention of diseases.
Heber D.
UCLA Center for Human Nutrition, Los Angeles , CA , USA . dheber@mednet.ucla.edu
The intake of 400-600 g/d of fruits and vegetables is associated with reduced incidence of many common forms of cancer, and diets rich in plant foods are also associated with a reduced risk of heart disease and many chronic diseases of ageing. These foods contain phytochemicals that have anti-cancer and anti-inflammatory properties which confer many health benefits. Many phytochemicals are colourful, and recommending a wide array of colourful fruits and vegetables is an easy way to communicate increased diversity of intake to the consumer. For example, red foods contain lycopene, the pigment in tomatoes, which is localized in the prostate gland and may be involved in maintaining prostate health, and which has also been linked with a decreased risk of cardiovascular disease. Green foods, including broccoli, Brussels sprouts and kale, contain glucosinolates which have also been associated with a decreased risk of cancer. Garlic and other white-green foods in the onion family contain allyl sulphides which may inhibit cancer cell growth. Other bioactive substances in green tea and soybeans have health benefits as well. Consumers are advised to ingest one serving of each of the seven colour groups daily, putting this recommendation within the United States National Cancer Institute and American Institute for Cancer Research guidelines of five to nine servings per day. Grouping plant foods by colour provides simplification, but it is also important as a method to help consumers make wise food choices and promote health.
PMID: 15235216 [PubMed - in process]
Nutr Rev. 2004 May;62(5):204-11 Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials.
Moyers SB, Kumar NB.
Department of Cancer Control and Nutrition, H. Lee Moffitt Cancer Center and Research Institute, Tampa , Florida , USA .
Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials.
Publication Types: Review Review, Tutorial
PMID: 15212320 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Lung Cancer. 2004 Jul;45(1):11-8. Neuroendocrine lung carcinogenesis in hamsters is inhibited by green tea or theophylline while the development of adenocarcinomas is promoted: implications for chemoprevention in smokers.
Schuller HM, Porter B, Riechert A, Walker K, Schmoyer R.
Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
Lung cancer continues to be the leading cause of cancer death in developed countries. With smoking the major etiological factor for lung cancer, there is a great need for the development of chemopreventive treatments that inhibit the progression of initiated cells and premalignant lesions into overt lung cancer in smokers who quit. Although the major focus of chemoprevention research has been on agents that inhibit the metabolic activation of genotoxic chemicals contained in tobacco products, some of these agents may additionally modulate growth-regulating signal transduction. In turn, the function of such signaling pathways is highly cell type-specific, with a given pathway inhibiting the growth of one cell type while stimulating the growth of others. The current experiment has tested the hypothesis that green tea and the methylxanthine theophylline contained in tea inhibit the progression of neuroendocrine lung carcinogenesis in hamsters with hyperoxic lung injury and initiated with the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) while promoting the development of Clara cell-derived pulmonary adenocarcinomas initiated by NNK in healthy hamsters. This hypothesis is based on published evidence that human small cell lung cancer as well as the neuroendocrine hamster tumors are regulated via autocrine signaling pathways that activate Raf-1 and the mitogen-activated (MAP) kinase pathway whereas human pulmonary adenocarcinomas of Clara cell lineage and the hamster model of this cancer type are regulated by a beta-adrenergic pathway involving the activation of cyclic adenosine 3',5'-monophosphate (cAMP) and the arachidonic acid (AA) cascade. In turn, it was hypothesized that theophylline would inhibit Raf-1-dependent tumor progression while promoting cAMP-dependent tumor progression due to its documented ability to inhibit the enzyme cAMP-phophodiesterase. The experimental design simulated chemoprevention in former smokers in that treatments with tea or theophylline started after completion of a 10-week tumor induction period with NNK. Our data show that green tea as well as theophylline significantly inhibited lung tumor multiplicity in the neuroendocrine cancer model whereas identical chemopreventive treatments significantly promoted the lung tumor multiplicity in the adenocarcinoma model. These findings indicate that green tea and theophylline as well as other chemopreventive agents that modulate signal transduction may have opposite effects on cancers of different histolopathology and cell lineage. At the current state of knowledge such chemopreventive treatments should only be used as adjuvant to cancer therapy of cancers that have been fully characterized at the pathology and molecular level.
PMID: 15196729 [PubMed - in process]
Curr Med Chem. 2004 Jun;11(11):1451-60. Antimicrobial and chemopreventive properties of herbs and spices.
Lai PK , Roy J.
Department of Bioscience, Salem International University , Salem , West Virginia 26426 , USA . roy@salemiu.edu
Herbs and spices have been used for generations by humans as food and to treat ailments. Scientific evidence is accumulating that many of these herbs and spices do have medicinal properties that alleviate symptoms or prevent disease. A growing body of research has demonstrated that the commonly used herbs and spices such as garlic, black cumin, cloves, cinnamon, thyme, allspices, bay leaves, mustard, and rosemary, possess antimicrobial properties that, in some cases, can be used therapeutically. Other spices, such as saffron, a food colorant; turmeric, a yellow colored spice; tea, either green or black, and flaxseed do contain potent phytochemicals, including carotenoids, curcumins, catechins, lignan respectively, which provide significant protection against cancer. This review discusses recent data on the antimicrobial and chemopreventive activities of some herbs and spices and their ingredients.
PMID: 15180577 [PubMed - in process] J Agric Food Chem. 2004 Jun 2;52(11):3583-9. Polyphenolic compounds, antioxidant capacity, and quinone reductase activity of an aqueous extract of Ardisia compressa in comparison to mate (Ilex paraguariensis) and green (Camellia sinensis) teas.
Chandra S, De Mejia Gonzalez E.
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 228 ERML, MC-051, 1201 W Gregory Drive, Urbana, Illinois 61801, USA.
Aqueous extracts of the leaves of Ardisia compressa (AC) have been used in folk medicine to treat various liver disorders including liver cancer. The objective of this study was to partially characterize and determine the total polyphenol content, antioxidant capacity, and quinone reductase activity of A. compressa tea in comparison to mate (Ilex paraguariensis, MT) and green (Camellia sinensis,GT) teas. Total polyphenol content, antioxidant capacity, and phase II enzyme induction capacity were measured by the modified Folin-Ciocalteu, ORAC, and quinone reductase (QR) assays, respectively. The major polyphenols in AC were not catechins. HPLC retention times and standard spikes of AC indicated the presence of gallic acid, epicatechin gallate, ardisin and kaempferol. Using catechin as standard, the total polyphenol value of AC (36.8 +/- 1.1 mg/mg DL) was significantly lower than GT (137.2 +/- 5.8 mg equivalent of (+)-catechin/mg dried leaves, DL) and MT (82.1 +/- 3.8 mg/mg DL) (P < 0.001). Antioxidant capacity (AC, 333; GT, 1346; MT, 1239 mmol Trolox equivalents/g DL) correlated with total polyphenol values (r(2) = 0.86, P < 0.01). AC (4.5-12.5 microg/mL) induced QR enzyme, in Hepa1c1c7 cells, up to 15%. MT and GT showed no induction at the concentrations tested (0.5-10.5 and 0.5-12.5 mg/mL, respectively). These results suggest that AC has a different mechanism of protection against cytotoxicity that is not related to its antioxidant capacity. Further studies are needed to determine such mechanisms and to explore its potential as a chemopreventive or therapeutic agent.
PMID: 15161234 [PubMed - indexed for MEDLINE]
Anticancer Res. 2004 Mar-Apr;24(2B):747-53. EGCG blocks tumor promoter-induced MMP-9 expression via suppression of MAPK and AP-1 activation in human gastric AGS cells.
Kim HS, Kim MH, Jeong M, Hwang YS, Lim SH, Shin BA, Ahn BW, Jung YD.
Chonnam University Research Institute of Medical Sciences, Chonnam National University Medical School , Kwangju , Korea .
Overexpression of matrix metalloproteinases (MMPs) has been known to correlate closely with tumor cell invasion and strategies to down-regulate their expression may ultimately be of clinical utility. In this study, we investigated the effects of (-)-epigallocatechin gallate (EGCG), a major green tea catechin, on the cell invasiveness and MMP-9 induction in human gastric cancer AGS cells. EGCG inhibited the phorbol 12-myristate 13-acetate (PMA)-induced cell invasiveness and MMP-9 expression in a dose-dependent manner. EGCG treatment was found to reduce the MMP-9 transcriptional activity. To further study the mechanisms for the EGCG-mediated regulation of MMP-9, the effects of EGCG on transcription factor AP-1 and mitogen-activated protein kinase (MAPK) activities were examined. The results showed that EGCG suppressed the PMA-induced AP-1 activation. EGCG also abrogated the PMA-induced activation of extracellular-regulated protein kinase (Erk) and c-jun N-terminal kinase (JNK), which are upstream modulators of AP-1. These results suggest that EGCG may exert at least part of its anti-invasive effect in gastric cancer by controlling MMP expression through the suppression of MAPK and AP-1 activation.
PMID: 15161022 [PubMed - in process] BJU Int. 2004 May;93(7):1082-6 Growth inhibition and cell cycle arrest effects of epigallocatechin gallate in the NBT-II bladder tumour cell line.
Chen JJ, Ye ZQ, Koo MW.
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong , Hong Kong , China .
OBJECTIVES: To examine the growth inhibition and cell cycle arrest effects of epigallocatechin gallate (EGCG), a major constituent of green tea polyphenols, on the NBT-II bladder tumour cell line. MATERIALS AND METHODS: Growth inhibition and cell cycle arrest effects of EGCG were evaluated by the tetrazolium assay, flow cytometry and apoptotic DNA ladder tests. The cell cycle-related oncogene and protein expressions in NBT-II bladder tumour cells, when incubated with EGCG, were detected with reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. RESULTS: EGCG inhibited growth of the NBT-II bladder tumour cells in a dose- and time-dependent manner. Flow cytometry showed a G0/G1 arrest in cells when cultured with EGCG at doses of 10, 20 or 40 micro mol/L for 48 or 72 h. The apoptotic DNA ladder test showed that EGCG at 10 micro mol/L induced early apoptosis after 48 h of incubation. A down-regulation of cyclin D1 was detected by RT-PCR when the cells were incubated with EGCG (20 micro mol/L for 48 h. EGCG also down-regulated protein expression of cyclin D1, cyclin-dependent kinase 4/6 and phosphorylated retinoblastoma protein, in both a time- and dose-dependent manner, when detected by Western blot. CONCLUSION: EGCG had growth inhibition and cell-cycle arrest effects in NBT-II bladder tumour cells by down-regulating the cyclin D1, cyclin-dependent kinase 4/6 and retinoblastoma protein machinery for regulating cell-cycle progression.
PMID: 15142168 [PubMed - indexed for MEDLINE]
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