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Critical Reviews in Food Science and Nutrition

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Green Tea: Nature's Defense against Malignancies

Masood Sadiq Butt & Muhammad Tauseef Sultan
a a a

National Institute of Food Science and Technology, University of Agriculture, Faisalabad

Available online: 27 Apr 2009

To cite this article: Masood Sadiq Butt & Muhammad Tauseef Sultan (2009): Green Tea: Nature's Defense against Malignancies, Critical Reviews in Food Science and Nutrition, 49:5, 463-473 To link to this article: http://dx.doi.org/10.1080/10408390802145310

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Critical Reviews in Food Science and Nutrition, 49:463473 (2009) Copyright C Taylor and Francis Group, LLC ISSN: 1040-8398 DOI: 10.1080/10408390802145310

Green Tea: Natures Defense against Malignancies

MASOOD SADIQ BUTT and MUHAMMAD TAUSEEF SULTAN
National Institute of Food Science and Technology, University of Agriculture, Faisalabad

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The current practice of introducing phytochemicals to support the immune system or ght 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 inammatory 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, inammation 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. Keywords green tea, nutritional support, oxidative stress, immunity, epigallocatechin-3-gallate, malignancies

INTRODUCTION Nutritional support is a recent development, prior to which the value of food was recognized for its medicinal benets as nutraceuticals. Nutraceuticals are widely accepted as an adjunct to conventional therapies for enhancing general wellbeing. The value of such alternative therapy is now being rediscovered by many researchers that support the use of traditional remedies to cure maladies (Klein et al., 2000; Ramaa et al., 2006). Micronutrients like antioxidants, plant sterols, and avonoids have shown several therapeutic potential against various health risks (Messina and Messina, 2003; Thurnham, 1999). Evidence has been provided that dietary phytochemicals may play important roles as chemopreventive or chemotherapeutic agents in the prevention of many diseases, possesses antimutagenic effects and indeed modulating and stimulating

Address correspondence to Masood Sadiq Butt. E-mail: drmsbutt@ yahoo.com

the immune system (Raskin et al., 2002; Rates, 2001) that in turn results in normal functioning of the whole body. Various plants and their constituents have shown benecial therapeutic effects, including anti-oxidant, anti-inammatory, anti-cancer, and immunomodulatory effects and green tea is one of them (Miller et al., 2004; Huffman, 2003; Parab et al., 2003; Fong, 2002). The plant of tea (Camellia sinensis) has been grown in Southeast Asia for thousands of years and now is cultivated in more than 30 countries around the world. Its consumption has reached a point where it has become the second most commonly consumed beverage worldwide. This popularity was due to its characteristic aroma, avor, and most inuencing its health benets (Ahmad et al., 1998; Harbowy and Balentine, 1997). The basic steps of manufacturing the various forms of teas (Black, Green, and Oolong) are similar, except in the development of their aroma and in the fermentation process, which is dependent on the oxidation states of catechins present in tea leaves. It is estimated that about 2.5 million metric tons of tea is manufactured annually (Hara, 2001; Katiyar and Mukhtar, 1996).

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The term green tea refers to the product manufactured from fresh tea leaves by steaming or drying at elevated temperatures with the precaution to avoid oxidation of the polyphenolic components (Chow and Kramer, 1990). Polyphenol oxidase (PPO) is mainly responsible for catalyzed oxidation of tea leaf catechins (Wilson and Clifford, 1992). Oolong tea is semifermented while black tea is a nearly fully fermented product and their processing involves the oxidation reaction catalyzed by PPO (Obanda et al., 2001). These reactions favor condensation of catechins with orthoquinones to form theaavins which subsequently reacts with gallic acid to form epitheaavic acid and together all these products are termed as thearubigins (Karori et al., 2007). Fermentation and enzymatic oxidations brings out the difference in compositions of different types of tea.

quercetin), caffeic acid derivatives, triterpene saponins, and volatile oils (Medical Economics Company (US), 2000; Dolby and Mitscher, 1998). Polyphenols account for the pungency and the unique avor of green tea. Catechins and other polyphenols present in green tea are antioxidant and anti-inammatory in nature and have been shown to possess anticarcinogenic activity (Baliga and Katiyar, 2006). The biological activity of green tea is due to different catechins and EGCG is identied as the principal antioxidant contributing approximately 30% of the total antioxidant capacity of green tea and has been recognized as the major and potentially effective chemopreventive agent present in green tea leaves (Stewart et al., 2005; Ahmad et al., 1998; Katiyar and Mukhtar, 1996).

Type of tea

% share in consumption 78% 20% 2%

Countries Western countries and some Asian countries Asian countries mainly Japan, China, Korea & India Southeastern China

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Black tea Green tea Oolong tea

Sources: Hara (2001); Katiyar and Mukhtar (1996)

BOTANICAL CLASSIFICATION Kingdom Subkingdom Superdivision Division Class Subclass Order Family Genus Species Plantae Plants Tracheobionta Vascular plants Spermatophyta Seed plants Magnoliophyta Flowering plants Magnoliopsida Dicotyledons Dilleniidae Theales Theaceae Tea family Camellia L. camellia Camellia sinensis (L.) tea

CHEMISTRY OF GREEN TEA RADICAL SCAVENGING ACTIVITYIES Like most herbs, the precise composition of green tea varies with the geographic origin of the leaf, the time of harvest, and processing techniques. Dried tea leaves are mainly composed of polyphenols (1025%), principally avonols (including catechins), avonoids, and avondiols. The leaves also contain plant alkaloids (about 4%) including caffeine, theobromine, and theophylline. Other constituents include proteins, carbohydrates, phenolic acids, minerals (including uoride and aluminum), and ber (Yang and Landau, 2002; Dolby and Mitscher, 1998; Kaegi, 1998; Mukhtar et al., 1994; Weisburger, 1992). The health-promoting properties of the tea plant often refers to active ingredients that includes polyphenols {epigallocatechin-3-gallate (EGCG), epicatechin, epicatechin3-gallate, epigallocatechin}, purine alkaloids {caffeine (2.9 4.2%), theobromine (0.150.2%), theophylline (0.020.04%)}, inorganic ions uoride, potassium, aluminum, avonoids (e.g. Reactive oxygen species can potentially lead to damage of almost all types of biological molecules including DNA, lipids, proteins, and carbohydrates (Valko et al., 2007). Oxidative stress results after the excessive production of reactive oxygen species that overrides the antioxidant capability of the target cells (Vina et al., 2006; Opara, 2004). Outcomes are DNA damage, production of mutated tumor-suppressor genes, and inducing cell death (Farah, 2005; Kang et al., 1997). These pathological events are involved in cardiovascular, neurodegenerative, and carcinogenic processes (Mobley and Brueggemeier, 2004; Ferrari, 2004). Improved antioxidant defence results in reduced prevalence of diseases associated with oxidative stress (Blomhoff, 2004; Ji and Peterson, 2004). The production of free radical depends upon various extrinsic and intrinsic factors. Generally these free radicals have been

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Figure 1

Structures of polyphenols present in green tea.

implicated in playing a role in more than 100 diseases that also includes cancer, atherosclerosis, and arthritis. Although human cells possess a large number of endogenous antioxidants but still certain amounts of exogenous antioxidants are constantly required to maintain an adequate level of antioxidants in order to balance the reactive oxidative species in the human body. Antioxidants protect the body by neutralizing the free radicals and donating one of their own electrons, thus ending the scavenger reaction. They have been found to be quite successful in the prevention of certain diseases for years especially cancer (Berger, 2005; Thomas, 1995; Frankel, 1984). Isbrucker et al., (2006) examined the antioxidant activities of water extracts of the various teas including the reducing power, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, and the inhibition of hemolysis caused by 2,2 -azobis(2-amidinopropane) dihydrochloride (AAPH)-induced lipid oxidation in erythrocyte membranes and they supported the use of green tea as a potential antioxidant. The chemical, in vitro and biological assays, demonstrated green tea polyphenols as strong antioxidants in their activity against iodophenol-derived phenoxyl radicals, superoxide anion radicals, and lipid peroxidation in rat liver microsomes (Zhang and Shen, 1997; Katiyar and Mukhtar, 1996). Salah et al., (1995) reported that the tea extracts are powerful antioxidants, mainly owing to the presence of (+)-catechin, ()-epicatechin, ()-epigallocatechin, ()-epigallocatechin gallate (EGCG), and ()-epicatechin gallate. EGCG is a valuable scavenger of reactive oxygen species and has strong antioxidant activity (Norwood et al., 2006; Bagchi,

1999). It protects cellular damage by inhibiting DNA damage and oxidation of LDL and many putative health benets of tea are presumed to be caused by its antioxidant effects. EGCG can reduce the inammatory response associated with local tissue injuries such as the hepatocellular necrosis in acute liver injury induced by carbon tetrachloride. The protective effects of EGCG are due to its ability to decrease lipid peroxidation, oxidative stress, and the production of nitric oxide (NO) radicals by inhibiting the expression of iNOS. It also ameliorates the overproduction of pro-inammatory cytokines and mediators, reduces the activity of NF-kappa-B and AP-1, and the subsequent formation of peroxynitrite with NO and reactive oxygen species (Tipoe et al., 2007). Thus, green tea or EGCG effectively mitigates cellular damage by lowering the inammatory reaction and reducing the lipid peroxidation and NO generated radicals leading to the oxidative stress. Green tea is proposed as a dietary supplement in the prevention of cardiovascular diseases and other diseases in which oxidative stress and proinammation are principal causes.

IMMUNOMODULATORY AND ANTI-INFLAMMATORY EFFECTS Immunity is considered as the ability of an organism to ght against any abnormal function occurring within the body and the immune system prevents infections and diseases by moderating malignant and foreign cells within the body (Schulenburg et al., 2007). The humans immune system is composed of

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organs like spleen and thymus while additionally lymph nodes and bone marrow also contribute to the proper immune functioning by producing and storing specic immune cells (SchmidHempel, 2005). Green tea enhances humoral and cell-mediated immunity decreasing the risk of certain cancers and the risk of cardiovascular disease (Klein et al., 2000). Polyphenols are the active ingredients in green tea that hold antioxidant, antiinammatory, and anti-carcinogenic properties and such health benets of tea are mainly attributed to its polyphenols contents (Higdon and Frei, 2003; Katiyar et al., 2001). Inammation is an integral part of the immune system but sometimes becomes a causative agent in causing some diseases (Bystrianyk, 2005). Dona et al., (2003) provide molecular and cellular insights into the claimed benecial properties of green tea and indicated that epigallocatechin-3-gallate (EGCG) is potent anti-inammatory compound with therapeutic potential. Studies in animal models show that green tea polyphenols decrease inammation. It has been reported that mice fed on the extract of green tea polyphenols had decreased the tumor necrosis factor- (TNF) production in response to an injection of lipopolysaccharide (LPS) and prevented death after administration of a lethal dose of LPS (Yang et al., 1998). The ingestion of a green tea polyphenol extract reduces joint disease in mice with adjuvant-induced arthritis and their consumption reduces disease activity in the autoimmune disease models like interleukin-2 decient mice (Haqqi et al., 1999; Varilek et al., 1999). These studies suggest that green tea may have benets in treating inammatory disorders. Several chemicals are used to induce inammatory responses that are further used to study anti-inammatory properties of various agents. Topical application of phorbol esters like TPA is one of them. These inammatory responses include epidermal hyperplasia, inammation, increase in the number of dark basal keratinocytes, and induction of epidermal ornithine decarboxylase (ODC) activity followed by an increase in the levels of polyamines. Further, ODC plays an essential role in cell proliferation and differentiation. Induction mediated by TPA is believed to be governed by cyclooxygenase and lipoxygenase catalyzed metabolites of arachidonic acid, specically prostaglandins and hydroxyeicosatetraenoic acids, respectively (Agarwal and Mukhtar, 1993; Agarwal and Mukhtar, 1991). Several controlled studies involving TPA, topical application of green tea polyphenols (GTP) to mouse skin inhibits TPA-mediated induction of epidermal ODC activity in a dosedependent manner (Agarwal et al., 1993). GTP prevents TPAinduced oxygen radical-induced cytotoxicity, inhibits intercellular communication in normal human epidermal keratinocytes, and inhibits TPA-induced protein kinase-C activity (Ruch et al., 1989; Yoshizawa et al., 1987). Topical application of GTP to mouse skin inhibits 12-0-tetradecanoylphorbol-13-acetate and other skin tumorpromoter-caused induction of protein and mRNA expression of the pro-inammatory cytokines interleukin (1L)-1 and TNF- . Skin applications of green tea polyphenols inhibits UVradiation-induced local and systemic suppression of contact

hypersensitivity and edema responses in C3H/HeN mice. In many in vitro studies, green tea polyphenols/crude extracts of green tea have shown to have preventive effects on the system considered essential in inammatory processes (Ahmad et al., 1997; Katiyar and Mukhtar, 1996). Skin application of GTP to SENCAR mice resulted in significant protection against TPA-caused effects on cyclooxygenase and lipoxygenase activities. Katiyar et al., (1992c) elaborated that prior application of GTP onto the dorsal skin of mice results in signicant inhibition of TPA-mediated epidermal edema and hyperplasia. Pre-application of GTP can also protect signicantly against TPA-induced hyperplasia in the ear skin and TPAcaused inltration of polymorphonuclear leukocytes (Katiyar et al., 1993). Toll-like receptors (TLRs) play an important role in recognition of microbial components and induction of innate immunity. The microbial components trigger the activation of two downstream signaling pathways of TLRs; MyD88- and/or TRIF-dependent pathways leading to activation of NF-kappaB. (-)-Epigallocatechin-3-gallate (EGCG), a avonoid found in green tea, is known to inhibit NF-kappa-B activation induced by many pro-inammatory stimuli. Green tea avonoids modulate MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inammatory target gene expression (Youn et al., 2006). Several studies have focused on potential mechanisms responsible for the anti-inammatory and anticancer effects. One potential mechanism of action is the inhibition of nuclear factor B activation. Nuclear factor- B is an oxidative stress-sensitive transcription factor that regulates the expression of a variety of genes important in cellular responses, including inammation, innate immunity, and growth. EGCG decreased LPS-induced TNF production in the macrophage cell line RAW264.7 and peritoneal macrophages by blocking NF- B activation (Yang et al., 1998). In a similar study, Lin and Lin (1997) suggested that EGCG inhibits LPS-induced inducible nitric-oxide synthase gene expression in mouse peritoneal macrophages by decreasing the expression of the transcription factor, NF- B.

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MALIGNANCIES AND GREEN TEA Cancer is generally considered as uncontrolled cell division that results in the aggregation of cells to form tumors. There are many factors which are involved in the pathogenesis of cancers, e.g. genetic mutations, smoking, heavy metal ingestion, and other pollution and indeed lack of proper diet. The immune system plays a crucial role and inammation eventually causes aggregation of cells due to disturbances in signaling pathways that are associated with the pathogenesis of cancers (Noonan et al., 2007). The initial step in carcinogenesis involves the metabolic activation of chemical carcinogens by the P-450-dependent biotransformation reaction (Mukhtar et al., 1991). Cytochrome P450 is the major enzyme system responsible for the metabolism of procarcinogens to their DNA binding metabolites. This

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binding to DNA is considered essential for tumor initiation (Agarwal and Mukhtar, 1991). Inammation is a key component in cancer insurgence that can promote tumor angiogenesis which is necessary for solid tumor growth. Controlling such mechanisms of inammation and controlled cell death are key targets of most chemopreventive agents (Noonan et al., 2007). Harmlessly disposing of cancer cells is one of the main considerations in chemotherapy (Chan et al., 1997). Cell death can occur by either of two distinct mechanisms: necrosis (accidental cell death) and apoptosis (programmed cell death). A variety of pharmacological and physiological agents can trigger the cascade of events that leads to apoptosis. The life span of both normal and cancer cells within a living system is signicantly affected by the rate of apoptosis. Chemopreventive agents that could modulate apoptosis might affect the steadystate cell population (Fesus et al., 1995). Therefore, it can be assumed that the chemopreventive agents with proven effects in animal tumor bioassay systems and human epidemiology and the ability to induce apoptosis of cancer cells, may have wider implications for the management of cancer. Flavanols are groups of chemicals that possess strong nucleophilic centers at two positions. This property provides an opportunity for the avanols to react with electrophilic carcinogenic species to form avonol-carcinogen adducts that may result in the prevention of tumorigenesis. Catechins and polyphenols from green tea show the anticancer activity. The anti-carcinogenic and anti-mutagenic activity of polyphenolic agents present in green tea were rst reported almost couple of decade ago (Colic and Pevelic, 2000; Khan et al., 1988; Wang et al., 1989a; b). Green tea has shown in experimental animal studies, human cell line laboratory studies, and also epidemiologically in large human population studies that it could signicantly reduce the risk, protect from or prevent several cancers, and improve treatment that includes the treatment of the biliary tract, bladder, breast, and colon cancer (Takada et al., 2002; Kamat and Lamm, 2002; Berger et al., 2001; Sartippour et al., 2002; Hong et al., 2002). Green tea is also effective in leukemia (Smith and Dou, 2001), liver, and lung cancer (Bertram and Bartsch, 2002; Fujimoto et al., 2002). Some other scientic studies reported its benecial effects in esophageal, prostate, and skin cancer (Youn et al., 2006; Mantena et al., 2005; Gupta et al., 2003; Proniuk et al., 2002; Liao, 2001; Katiyar and Mukhtar, 1997). Much of the cancer chemopreventive properties of green tea are mediated by EGCG and it has been assumed that it induce apoptosis and promote cell growth arrest by altering the expression of cell cycle regulatory proteins, altering Bax/Bcl2 function, activating killer caspases, and suppressing nuclear factor kappa-B function. EGCG modulates the signal transduction pathways involved in cell proliferation, transformation, inammation, apoptosis, and metastasis (Khan et al., 2006; Na and Surh, 2006; Gupta et al., 2004). Although different hypotheses are presented for its chemopreventive mechanism but still needs the attention of researchers to carry out joint research programs to capture its true mechanism of actions.

Colon Cancer Several population-based studies have shown that green tea helps protect against colon cancer. For example, cancer rates tend to be low in countries such as Japan where people regularly consume green tea. However, it is not possible to determine from these population-based studies whether green tea actually prevents cancer in people. Researchers also believe that polyphenols help kill cancerous cells and stop their progression. Emerging studies suggested that the polyphenols in green tea may play an important role in the prevention of colon cancer (Bushman, 1998). There are several factors that are associated with the onset and progression of colon cancer and several lines of mechanism have been presented for the action of green tea or its active ingredients. EGCG treatment to colon cancer cells results in strong activation of AMPK, an inhibition of COX-2 expression. Increased expression of COX-2 appears to play an important role in the development of colorectal cancer (Shimizu et al., 2005). The activation of AMPK with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells supports the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells (Hwang et al., 2007). EGCG inhibited COX-2 mRNA and protein overexpression. The effect of EGCG on COX-2 expression resulted in decreased COX-2 promoter activity via inhibition of nuclear factor kappa-B activation (Lambert et al., 2006; Balavenkatraman et al., 2006). Peng et al., (2006) observed that EGCG down-regulated the ERK1/2 and Akt pathways in colon cancer cells. The transmembrane protein-tyrosine phosphatase DEP-1 (density-enhanced phosphatase) is a potential candidate for tumor suppression in the colon epithelium. Upregulation of DEP-1 expression, and in turn inhibition of cell growth and migration may present another possible unrecognized mechanism of chemoprevention and green tea polyphenols had the capacity to elevate transcription of endogenous DEP-1 mRNA and expression of DEP-1 protein (Jeong et al., 2004). EGCG reduces LPS-induced Ikappa-Balpha phosphorylation, potently inhibited cell growth, and induces Caspase-3 activity. These are important signaling pathways and EGCG imparts a potential biological function to cater to its chemopreventive properties. In another study, Chen et al., (2003) observed that EGCG inhibited HT-29 cell growth with an IC50 of approximately 100 microM after 36 h treatment. Their observation also includes Caspase-3 and Caspase-9 activation, mitochondrial transmembrane potential transition, and cytochrome c release and as an early signaling event was activation of MAPKs. Inhibition of c-Jun N-terminal kinase (JNK) pathway shows that the involvement of JNK in EGCG-induced cytochrome-c release and cell death. Jia and Han, (2001) investigated the effect of green tea on 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation in Wistar rats and concluded that green tea drinking inhibits ACF formation in rats, and such effects may

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relate to the suppression of cell proliferation in the intestinal crypts. Some studies on the effects of green tea on colon or rectal cancer produced conicting results. EGCG when compared to the chemotherapeutic drug of choice, 5-uorouracil (5-FU) have some comparable chemotherapeutic responses to the SW-626 cell line (Zhang and Shen, 1997) which indicates that EGCG has a similar response in decreasing cell number with 5-FU. Population-based studies showed decrease risk in those who drink tea, while in some instances researchers showed increased risk. Further research is needed before researchers can recommend green tea for the prevention of colorectal cancer.

Skin Cancer Skin cancer represents a major, and growing, public health problem. It has been estimated that more than one million new cases of skin cancers are diagnozed each year in the United States alone, which is equivalent to the incidence of malignancies in all other organs combined (Housman et al., 2003). Skintumor promotion is divided into stages known as stage I and stage II (Agarwal and Mukhtar, 1993). TPA is widely employed as tumor promoter in two-stage skin tumorigcnesis protocols. Topical application or oral feeding of a polyphenolic fraction isolated from green tea, referred to as GTP, to SENCAR, CD-1 and Balb/C mice results in signicant protection against skin tumorigenesis (Mukhtar et al., 1992, Katiyar et al., 1992b). Topical application of GTP concurrently with each application of either TPA (anti-stage I) or mezerein (anti-stage II) for 7 d prior to the single application of 7,12-dimethylbenz(a)anthracene (DMBA) as the initiating agent followed by twice weekly applications of TPA results in signicant protection against tumorigenesis (Wang et al., 1989a). Mukhtar et al., (1994) also reported that a topical application of GTP results in signicant protection against tumor formation in DMBA-initiated SENCAR mouse, in terms of both tumor multiplicity (4250%) and tumor growth (4354%) Experimental studies involving animals, GTP application results in lower tumor body burden such as decrease in the total number of tumors per group, number of tumors per animal, tumor volume per mouse, and average tumor size. Topical application of GTP to CD-1 mice inhibited TPA-induced tumor promotion in DMBA-initiated skin and inhibits tumor promotion by TPA and other skin-tumor promoters such as teleocidin and okadaic acid (Katiyar et al., 1992c; Huang et al., 1992). In another intervention it was demonstrated that GTP interact with BP-7,8-diol 9,10-epoxide-2 and their topical application prior to BP-7,8-diol 9,10-epoxide-2 treatment results in inhibition of skin tumor initiation (Khan et al., 1988). GTP or EGCG when given intraperitoneal inhibits tumor growth and causes partial regression of established skin papillomas. Epidermal aryl hydrocarbon hydroxylase activity and epidermal enzyme-mediated binding of BP and DMBA to DNA was inhibited by these polyphenols (Wang et al., 1989a; Wang et al., 1989b).

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Ultraviolet B (UVB) radiation present in the solar spectrum is one of the major risk factors for skin cancer in humans (Elmets, 1991). Chronic oral feeding of 0.1% GTP in drinking water (w/v) to mice during the entire period of UVB exposure was found to result in signicantly lower tumor body burden as compared to non -GTP-fed (Wang et al., 1991). In another study, it was shown that infusion of green tea extracts as a sole source of drinking water (125%, w/v) to mice afforded protection against UVB radiation-induced intensity of red color and area of skin lesions, as well as UVB radiation-induced tumor initiation and tumor promotion (Wang et al., 1992a; b). Mechanisms of action behind EGCG action involves induction of terminal differentiation in epidermal keratinocytes and caspase-14, member of the caspase family associated with epithelial cell differentiation, planned cell death, and barrier formation (Hsu et al., 2007). Katiyar et al., (2007) reviewed the most recent investigations and elucidated that prevention of skin cancer is mediated involving different mechanisms and important considerations are given to the induction of immunoregulatory cytokine interleukin (IL) 12, IL-12-dependent DNA repair following nucleotide excision repair mechanism, the inhibition of UV-induced immunosuppression, the inhibition of angiogenic factors, and the stimulation of cytotoxic T cells in a tumor microenvironment (Meeran et al., 2006).

Lung Cancer Lung cancer, also called as bronchogenic cancer, is one of the most common cancers in the world and caused by the rapid growth and division of cells that make up the lungs. Treatment of lung cancer depends upon a variety of factors and histopathologic groupings into small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) may be used to better predict a patients response to chemotherapy. Small-cell lung carcinoma (SCLC) has a poor prognosis, particularly due to the development of drug resistance. Sadava et al. (2007) observed that incubation of human SCLC cells in EGCG for 24 h resulted in 5060% reduced telomerase activity and reduction in activities of caspases 3 (50%) and 9 (70%) but caspase 8 and DNA fragmentation remain unaffected with EGCG treatment. It has the capacity to block the cell-cycle in S phase indicating the potential use of EGCG, and possibly green tea, in treating SCLC. Liao et al., (2004) indicated that Polyphenon E extracted from green tea administration signicantly reduced the incidence (by 52%) and multiplicity (by 63%) of lung adenocarcinoma. Inhibition of angiogenesis and the induction of apoptosis by green tea may be closely related to the inhibition of pulmonary carcinogenesis (Lu et al., 2006). (-)-Epicatechin-enhanced apoptosis, growth inhibition of human lung cancer cell line PC-9 cells, while inhibition of TNF release from BALB/c-3T3 cells by EGCG and other tea polyphenols with a galloyl moiety in a dose-dependent manner reveals their possible potential against lung carcinoma (Suganuma et al., 1999).

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Signicant evidences are there that whole green tea is a more reasonable mixture for cancer prevention in humans than EGCG alone because it is more effective when it is used in combination with other cancer preventives. Mechanisms of green tea for chemoprevention of lung cancer includes antioxidant activity, phase II enzymes induction, inhibition of TNF expression and release, inhibition of cell proliferation, and induction of apoptosis. Inhibition of key protein kinases involved in cell cycle regulation and induction of apoptosis are probably the two most signicant effects launched by the utilization of green tea (Clark and You, 2006; Fujiki et al., 2002; Xu et al., 1992).

Prostate Cancer Prostate cancer is the most common male cancer in developed countries and is increasing in the developing world. Its long latency and geographical variation suggest the possibility of prevention or postponement of onset by dietary supplements (Jian et al., 2007). A number of epidemiological studies have suggested that consumption of green tea reduces the risk of prostate cancer. Because of unfavorable prognosis of extraprostatic, prevention is considered the best approach to ght it at the present time (Bettuzzi et al., 2007). Adhami et al., (2004) explored the role of green tea polyphenols in modulating the IGF-1driven molecular pathway in prostate tumor cells in a mouse model and their results were quite conclusive that the IGF-I/IGFBP-3 signaling pathway is a prime pathway for green tea polyphenolmediated inhibition of prostate cancer which limits the progression of cancer through inhibition of angiogenesis and metastasis. The treatment with tea ingredients results in (i) signicant inhibition in growth of implanted prostate tumors, (ii) reduction in the level of serum prostate specic antigen, (iii) induction of apoptosis accompanied with upregulation in Bax and decrease in Bcl-2 proteins and (iv) decrease in the level of VEGF protein (Siddique et al., 2006). EGCG inhibits COX-2 without affecting COX-1 expression at both the mRNA and protein levels, in androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells (Paschka et al., 1998). The inhibition induced by EGCG was found to occur via apoptotic cell death as shown by changes in nuclear morphology and DNA fragmentation (Hussain et al., 2005). Based on literature scanned, it can be suggested that a consumption of whole green tea or a combination of EGCG with chemotherapeutic drugs could be an improved strategy for prevention and treatment of prostate cancer.

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GTP and its principal constituent EGCG are effective in suppressing the proliferation of MDA-MB-231, a highly invasive estrogen receptor-negative breast cancer cell line as shown by growth inhibition and apoptosis induction (Thangapazham et al., 2006). Treatment of human MCF-7 cells with 50 microM EGCG can bring some positive changes as apoptosis, mitochondrial membrane potential changes, and activation of c-Jun N-terminal kinase (JNK), caspase-9 and caspase-3 (Hsuuw and Chan, 2007). In another study EGCG suppressed cell viability and induced apoptosis by the down-regulation of telomerase and inhibited angiogenesis by reducing the expression of vascular endothelial growth factor (VEGF) in a dose-dependent (Mittal et al., 2004; Sartippour et al., 2002). The rate of apoptosis and activity of caspase-3 induced by EGCG was time, and dose, dependent. These ndings suggest that EGCG might be useful in the treatment and/or prevention of breast cancer by inducing apoptosis. In vitro, epigallocatechin, another major catechin in green tea, also has strong effects in inducing apoptosis and inhibiting growth of breast cancer cells (Stuart et al., 2007; Zhao et al., 2006; Vergote et al., 2002). Epidemiologic studies have suggested that the regular consumption of tea, particularly green tea, moderately decreases the risk of cancer (Weiseburger et al., 1998). These results were all supported with meta-analysis carried out by Sun et al., (2006) and Zhang et al., (2007) gave conclusive ideas regarding prevention and eliminating the risk of breast cancer.

MECHANISM OF ACTION The studies suggested that multiple mechanisms are involved, including induction of apoptosis, cell cycle arrest downregulation of telomerase, inhibition of vascular endothelial growth factor, and suppression of aromatase activity (Stuart et al., 2007; Mittal et al., 2004; Way et al., 2004; Sartippour et al., 2002; Liang et al., 1999). The protective effects of green tea polyphenols have been attributed to the inhibition of enzymes such as the cytochromes P450, which are involved in the bio-activation of carcinogens. Studies have also shown the involvement of Phase II detoxication enzymes during the biological response to green tea. Because the 5 anking regions of Phase II genes contain an antioxidant-responsive element (ARE) which is believed to mediate the induction of Phase II enzymes by many drugs, the involvement of the MAPK pathway was studied by Yu et al., (1997) as a mechanism of biological response to green tea polyphenols. Their study provided evidence that the activation of the MAPK pathway might be due to a potential signaling pathway involved in the regulation of phase II enzyme gene expression. Enhancement of enzymatic pathways like glutathione peroxidase, catalase, NADPH-quinone oxidoreductase, and glutathione S-transferase activities that play a role in the detoxication of carcinogenic metabolites formation by P-450 are

Breast Cancer The most common malignancy in women worldwide is breast cancer. Several experimental studies explored that green tea has anticarcinogenic effects against breast cancer (Zhang et al., 2007; Zick et al., 2006).

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key determinants for cancer initiation and may be expected to have protective functions against carcinogenesis (Khan et al., 1992). The green tea polyphenols stimulate the transcription of Phase II detoxifying enzymes through ARE. Mukhtar and Ahmad, (1999) suggested that green tea polyphenol treatment results in signicant activation of MAPK, extracellular, signalregulated kinase-2 (ERK2), as well as JNK1 and an increase in the mRNA levels of early response genes c-jun and c-fas. Jankun et al., (1997) also highlighted the anti-cancer activity of EGCG and associated it with the inhibition of urokinase, is one of the most frequently expressed enzymes in human cancers. Fujiki et al., (1998) demonstrated that EGCG and other tea polyphenols inhibit growth of human lung cancer (PC-9) cells with a G2/M phase arrest of the cell cycle. The activation of the epidermal growth factor receptor (EGFR) tyrosine kinase by its ligand is believed to initiate multiple cellular responses associated with cell proliferation. Liang et al., (1997) elucidated that EGGG signicantly inhibit both DNA synthesis and the protein tyrosine activities of EGFR, platelet-derived growth factor receptor (PDGFR), and broblast growth factor receptor (FGFR). Pannala et al., (1997) attributed the ability of green tea polyphenols to (i) inhibition of OONO-mediated tyrosine-nitration, and (ii) limiting surface charge alteration of low density lipoprotein (LDL). Activation of AP-1 plays an important role in tumor promotion (McCarty, 1998). Dong et al., (1997) investigated the antitumor promoting effects of EGCG and theaavins and reported that both of these were found to inhibit EGF- or TPAinduced cell transformation, as well as AP-1-dependent transcriptional activity and DNA binding activity. He further found that the inhibition of AP-1 activation occurs via the inhibition of a c-Jun NH2-terminal kinase (JNK)-dependent pathway. Lu et al., (1998) investigated some possible mechanisms involved with the antiproliferation activity of EGC and demonstrated that it reduces the level of c-jun mRNA, phosphorylated JNK1, and JNK1-kinase activities.

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