Abstract
Consumption of green tea (Camellia sinensis) has been suggested to have beneficial health effect, including cancer prevention. Extensive studies have established that the active cancer preventive constituents in green tea are a group of polyphenols. Green tea polyphenols display anticancer activity in many organ sites in different experimental models in rodents and in cultured cell lines in vitro. Treatment with green tea polyphenols leads to the inhibition of cancer cell proliferation, cancer-associated angiogenesis, and metastasis, as well as the induction of cancer cell apoptosis. Experimental studies demonstrate that these activities are likely resulted from the antioxidant activity and the direct binding of green tea polyphenols to proteins, resulting in the modulation of multiple cellular signaling pathways. The findings of polyphenol binding proteins reveal the mechanisms of the effectiveness and specificity of the anticancer actions. However, the inverse association between of green tea consumption and cancer risk is supported by epidemiological studies, but not all. This inconsistence may due to the lower blood and tissue levels of polyphenols from green tea drink, and may also depend on various etiology factors. Using much higher doses, results from some interventional studies support the safety and effectiveness of green tea polyphenols in cancer prevention. Well-designed clinical studies are required to fully evaluate the usefulness of green tea polyphenols in cancer prevention.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Anticancer Activity
- Epidermal Growth Factor Receptor Mutation
- Aberrant Crypt Focus
- Gastric Cancer Risk
- Lewis Lung Carcinoma Cell
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
4.1 Introduction
The consumption of green tea, a beverage derived from the dried leaves of the Camellia sinensis plant, has a long history in Asia and is believed to have beneficial health effects such as preventing cancer, diabetes, neurodegeneration, eliminating toxic chemicals, anti-aging, improving cardiac function (Weisburger 1999, 2003; Yang et al. 2002; Higdon and Frei 2003; Lambert et al. 2005a; Yang et al. 2009a, b). Recent years, its cancer preventive activity has drawn the most attentions. Since 2000, there are over 2,000 research publications associated to tea and cancer. Extensive studies have established that there are two types of chemicals in green tea constituents, polyphenols and caffeine, responsible for cancer preventive activities (Conney et al. 2007; Yang et al. 2009a, b). The cancer preventive activity of polyphenols is the focus of this chapter.
Green tea catechin are a group of polyphenols, including (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), (−)-epicatechin (EC) and other minor catechins (Lambert et al. 2007; Yang et al. 2009a, b, 2011; Sang et al. 2011). Among them, EGCG is the most abundant and active constituent in green tea. The anticancer activity of green tea polyphenols has been demonstrated in many types of cancers in experimental modeling systems range from different cancer cells cultured in vitro to various animal models (Yang et al. 2002, 2011). Treatment with green tea polyphenols leads to the direct effects on cancer cells such as the inhibition of tumor cell growth and the induction of tumor cell apoptosis (Yang et al. 2002, 2009b, 2011; Lambert et al. 2005a). Such effects have been reported to involve not only the regulation of specific genes, but also the modulations of multiple cellular signaling pathways (Yang et al. 2002, 2009b, 2011; Lambert et al. 2005a). The cancer preventive activity may be a result of combinatory effects on multiple targets, although the relative importance of the different pathways may depend upon the cellular context. Despite a large body of experimental evidences supporting the anticancer activity of green tea polyphenols, epidemiology studies conducted to determine the potential inverse association between the consumption of green tea and human cancer risk has shown inconsistent results. Some epidemiological studies conclude that green tea consumption is associated with reduced cancer risk, whereas some studies suggest that green tea is not associated with the reduced cancer risk (Boehm et al. 2009; Yang et al. 2009b). Albeit there are only a few clinical studies on the application of green tea polyphenols in cancer prevention, it is suggested that higher doses of green tea polyphenols can be tolerated and effective in cancer prevention. Here, we review the experimental evidences of the biological activity of green tea polyphenols and discuss the existing data from epidemiology and clinical studies regarding whether green tea polyphenol is effective in reducing human cancer risk in order to understand the potential application of green tea polyphenols for cancer prevention.
4.1.1 Tea Constituents and Their Biochemical Properties
A typical cup of green tea, brewed with 2.5 g of dry tea leaves in 250 mL hot water, contains 620–880 mg of water extractable chemicals among which tea polyphenols account for 30–42 % (Balentine et al. 1997). The major polyphenols are four catechins, EGCG, EGC, ECG, and EC, and their structures are shown in Fig. 4.1. The water extractable fraction is the green tea extract (GTE) and has often been used for numerous experimental studies in earlier years. Because EGCG is accounted for 50–80 % of the total catechins in tea, it is considered as the major tea catechin and purified EGCG has been used in substantial amount of studies. Thus the bioactivities of tea polyphenols are often represented by the activity of EGCG in many studies.
A well-defined activity of green tea polyphenols is the antioxidant activity, which is associated with the multiple phenolic groups on each ring: dihydroxyl or trihydroxyl substitutions on the B ring and the m-5,7-dihydroxyl substitutions on the A ring (Fig. 4.1) (Balentine et al. 1997). The B ring is the principle site of antioxidant reactions (Valcic et al. 2000; Meng et al. 2002), while the trihydroxyl D ring (gallate) of EGCG or ECG provides the extra potentials for antioxidant reactions. The polyphenolic structures allow electron delocalization and give green tea polyphenols ability to quench free radicals. Indeed, it is demonstrated that tea polyphenols are able to trap reactive oxygen and nitrogen species (RONS) including superoxide radical, singlet oxygen, hydroxyl radical, peroxyl radical, nitric oxide, nitrogen dioxide, and peroxynitrite (Balentine et al. 1997; Valcic et al. 2000; Meng et al. 2002). EGCG has the most hydroxyl groups (a total of eight hydroxyl groups) and is the most potent in reacting with RONS. Besides the direct mechanism to quench free radicals, green tea polyphenols are strong chelators of metal ions. Chelation of free metal ions by green tea polyphenols prevents the formation of reactive oxygen species (ROS) from the auto-oxidation of many compounds that requires metal ions.
However, the vicinal dihydroxy or trihydroxy structure of tea polyphenols not only contributes to the anti-oxidative activity, but also increases the susceptibility of these compounds to air oxidation under alkaline or neutral pH. This is a particularly important feature of EGCG as the auto-oxidation of EGCG in solution generates superoxide anion and hydrogen peroxide and leads to the formation of several unstable intermediates including EGCG quinone, quinone-dimer, and theasinensins (Yang et al. 2009b; Lambert and Elias 2010). It is worth noting that, in the cell culture experiment, the auto-oxidation of EGCG is enhanced in cell culture medium containing metal ions. For example, a half-life of EGCG less than 30 min was observed in McCoy’s 5A medium, commonly used for colon cancer cell line culture (Sang et al. 2007). By a real-time mass analysis, the kinetic of EGCG auto-oxidation at the concentrations of 50 and 200 μM in a Tris–HCl buffer (pH 7.2) has been elucidated (Sang et al. 2007). It has been proposed that oxygen reacts with EGCG to produce EGCG radical (EGCG·) and superoxide radical (O2 −·), both of which are unstable and active. This reaction is probably catalyzed by metal ions such as Cu2+ or Fe2+. Then O2 −· reacts with another EGCG molecule to produce EGCG· and hydrogen peroxide (H2O2). EGCG· reacts with oxygen to produce EGCG quinone and generate O2·−. O2·− can then react with another molecule of EGCG for the propagation of a chain reaction of EGCG auto-oxidation (Fig. 4.2), which produces significant amount of ROS.
ROS generated by the auto-oxidation of EGCG is given more attentions in our experimental system using cultured cells. We have found that EGCG is very effective in killing cultured cells as analyzed by cytotoxic or cell proliferation assays with effective concentration as low as 5 μM. This is due to the cytotoxicity of quinone and ROS. However, when we add superoxide dismutase (SOD) into the medium prior to the addition of EGCG to block O2 ·−, the cell killing effect is significantly reduced. The half maximal inhibitory concentration (IC50) of EGCG required for inhibiting cell proliferation at 48 h is determined to be around 30–50 μM. This issue is particularly important for evaluating the results of the studies on cell signaling mechanism using cultured cells since ROS is able to cause changes on variety of cell signaling pathways. For example, ROS contributes to the inactivation of epidermal growth factor receptor (EGFR) (Naasani et al. 2003; Hou et al. 2005). Thus, we strongly suggest the addition of SOD to remove O2·− and catalase to remove H2O2 for the prevention of EGCG auto-oxidation when EGCG is studied in cultured cells in vitro. This addition reduces the cytotoxic effect but does not change the biological action of EGCG. In our recent study identifying miR-210 up regulated by EGCG, we found no difference in the upregulation of miR-210 by EGCG in lung cancer cells in the presence or absence of SOD and catalase (Wang et al. 2011). On the other hand, the effect associated with the ROS produced by the EGCG auto-oxidation, such as its inhibition on TGF (Vittal et al. 2004) and EGF (Hou et al. 2005), is prevented by the addition of SOD. Thus, the addition of SOD and catalase to remove ROS in the medium can distinct whether the action is mediated by ROS produced by the auto-oxidation of EGCG.
4.1.2 Green Tea Polyphenol Biotransformation and the Activities of Metabolites
After drinking green tea, it takes about 1–1.5 h for green tea polyphenols to reach peak levels in the blood. When drinking an equivalent of two cups of green tea, the peak values of EGCG, EGC, and EC were 0.26, 0.48 and 0.19 μM, respectively (Lee et al. 2002). Considering the application of EGCG as the cancer prevention agent, pharmacological doses have been studied and the highest blood peak value reported were as high as 7 μM (Lee et al. 2002). In most animal and clinical studies, the peak blood levels were usually below 1 μM and the half life of EGCG was approximately 2–3.5 h (Lee et al. 2002; Lambert et al. 2008). These observed peak blood values of EGCG were lower than the concentrations of EGCG that were used in most mechanistic studies, which often are about 10–100 μM, in cell culture. Although local concentration of EGCG in cancer tissue may be different, these data about the peak blood levels should be used as references for designing experiments and evaluating the results from in vitro studies.
After ingestion, green tea polyphenols have been found to undergo extensive biotransformation, including methylation, glucuronidation, and sulfation, as well as the microbial metabolism (i.e. ring fission) in the digestion tracts (Yang et al. 2002; Feng 2006; Sang et al. 2011). In the plasma, most EGCG is unconjugated (Chow et al. 2001), whereas most of ECG, EGC and EC are in the glucuronidated or sulfated (Lee et al. 1995; Zhu et al. 2000; Yang et al. 2002). However, it is less clear how these processes affect the anticancer activity of green tea polyphenols. Some in vitro experimental results suggest that the inhibitory activities of EGCG metabolites on cancer cell growth are less effective than EGCG (Lambert et al. 2005b, 2006; Nakagawa et al. 2007). Thus, it is reasonable to assume that the anticancer activities of green tea polyphenols are not due to their metabolites. EGCG is mainly excreted through bile, whereas EGC is excreted in urine. Since the bioavailability of polyphenols is a key parameter for understanding this biological effect, to measure tea polyphenols and their metabolites may provide useful information.
4.2 Application of Green Tea Polyphenols in Cancer Prevention
Cancer prevention by green tea polyphenols has been extensively studied for many years from in vitro and in vivo models as well as epidemiology and clinical studies. The overall conclusions are that green tea polyphenols are effective in inhibiting or preventing cancer progression in the majority of animal models. However, not all epidemiology studies support the inverse association between green tea consumption and cancer risk.
4.2.1 Inhibition of Tumorigenesis in Animal Studies
Green tea polyphenols display inhibitory activity against carcinogenesis in animal models at many organ sites, including lung, oral cavity, esophagus, stomach, small intestine, colon, skin, prostate, breast, liver, bladder, pancreas and thyroid (Yang et al. 2009b, 2011; Yang and Wang 2011). Among the models, lung, colon, prostate, breast, and skin cancers have been investigated extensively and will be discussed in details as examples of our current understanding of this subject.
4.2.1.1 Prevention of Lung Carcinogenesis by Green Tea Polyphenols
Administration of green tea polyphenols has been demonstrated to be effective in inhibiting lung carcinogenesis in 19 out of 21 studies using mice, rats, and hamsters (Ju et al. 2007; Yang et al. 2009b). Among these animal models, the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or benzo[a]pyrene (B[a]P)-induced lung carcinogenesis draws the most attentions. NNK and B[a]P are the major carcinogens found in cigarette smoke and used to mimic cigarette smoke to induce lung cancer. In A/J mice, NNK treatment induces lung carcinogenesis with the development of adenoma within 20 weeks and the progression of adenoma to adenocarcinoma between 20 and 50 weeks (Hoffmann et al. 1996). When 0.5 % green tea polyphenol extract was given to A/J mice bearing NNK-induced lung tumors as drink fluid for 32 weeks, adenoma progression to adenocarcinoma was inhibited (Lu et al. 2006a). Further, EGCG has been demonstrated to inhibit the xenograft tumors of human lung cancer cell lines H1299 and H460 in nude mice (Li et al. 2010). Apoptosis specific in tumors and not in normal lung tissues was induced by EGCG treatment while pro-proliferation signaling (i.e. c-Jun and phospho-ERK1/2) in tumors were reduced (Lu et al. 2006a; Li et al. 2010). Differential gene expression had also been profiled in tumors from the mice treated with green tea polyphenol (Lu et al. 2006b). Together with other studies on lung cancer, green tea polyphenols display multiple activities in inhibiting different aspects of lung carcinogenesis in this experimental model.
4.2.1.2 Prevention of Colon Carcinogenesis by Green Tea Polyphenols
The cancer preventive activity of green tea polyphenols is also demonstrated in different colon cancer animal models (Ju et al. 2007; Yang et al. 2009b). First, EGCG significantly inhibits colon tumorigenesis in Apc min/+ transgenic mouse model. Administration of Apc min/+ transgenic mouse with 0.02–0.32 % EGCG as the drink fluid shows a dose-dependent inhibition on the tumorigenesis in the small intestine (Ju et al. 2005; Hao et al. 2007). EGCG treatment leads to reduced Wnt signaling activity as indicated by the increased level of E-cadherin, decreased level of nuclear β-catenin, and reduced level of Wnt target such as c-myc, and pro-proliferation signaling such as phospho-Akt and phospho-ERK1/2 (Ju et al. 2005). Second, EGCG inhibits the chemical carcinogen induced colon cancer in rodent models. The incidence of aberrant crypt foci (ACF), representing colonic premalignant lesion, in azoxymethane (AOM)-treated F334 rats is reduced significantly by 0.01 % EGCG in drinking water (Ohishi et al. 2002). Besides, 0.1 % EGCG in drinking water further inhibits the high-fat diet enhanced incidence of ACF in the AOM-treated CF-1 mice (Ju et al. 2003). However, the involved mechanism remains unclear.
4.2.1.3 Prevention of Prostate Carcinogenesis by Green Tea Polyphenols
Green tea polyphenols display inhibitory activity in mouse prostate cancer models in several studies (Ju et al. 2007; Yang et al. 2009b). In study using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, 0.1 % green tea polyphenols in drinking water is reported to be effective in inhibiting tumor incidence, burden, and metastasis (Gupta et al. 2001; Caporali et al. 2004). Similar to other cancer models, the pro-proliferation signalings (i.e. phospho-Akt and phospho-ERK1/2) are reduced in the prostate cancer of TRAMP model (Adhami et al. 2004). In this model, IGF-1 is reduced and IGFBP3 is increased (Adhami et al. 2004), which suggest that green tea polyphenols block IGF-1 signaling. However, these studies may not be sufficient to support the inhibitory activity of green tea polyphenols in prostate carcinogenesis. Prostate cancer developed in TRAMP model is androgen-independent and most of them are endocrine origin, whereas human prostate cancer is epithelial cell origin and hormone dependence in the earlier stage (Shen and Abate-Shen 2010). Thus, a proper model is necessary for addressing these issues for determining the effectiveness of the inhibition on prostate carcinogenesis.
4.2.1.4 Prevention of Breast Cancer by Green Tea Polyphenols
The studies of the anticancer activity of green tea polyphenols in mammary cancer in animal models are found to be somewhat inconsistent (Ju et al. 2007; Yang et al. 2011). Some studies show the anticancer activity of green tea polyphenols while others suggest no effect. The overall results can be seen in three different categories: potent inhibitory activity, partial inhibitory effect on certain aspect of mammary tumor, and no effect. It has been suggested that the poor bioavailability of green tea polyphenols in mammary gland tissues might be the reason behind these differences (Yang et al. 2011). Therefore, green tea polyphenols may not be able to target mammary cancer directly. The observed anticancer activity could be an indirect effect resulted from the inhibition of green tea polyphenols on other aspects such as inflammation or oxidative stress.
4.2.1.5 Prevention of Skin Cancer by Green Tea Polyphenols
Skin cancer can be treated by topical application, which overcomes the possible poor bioavailability as proposed in mammary gland tissue described above. Green tea polyphenols can be used more frequently and at higher concentrations. As matter of fact, this approach is very effective in treating mouse skin cancer by EGCG. For instance, topical application of EGCG to the skin in SKH-1 mice treated by UVB results in the reduction of tumor incidence, multiplicity, and size (Lu et al. 2002, 2005). Interestingly, the treatment of green tea polyphenols is found to also decrease adipose tissue in skin and the inhibition of UVB-induced skin cancer appears to be associated to the reduction of adipose tissue (Lu et al. 2001). It remains to be determined whether this phenomenon is a coincidence or an indirect inhibition of skin cancer.
4.2.2 Epidemiology Studies on the Association Between Consumption of Green Tea and Cancer Risk
Many epidemiology studies, including both cohort and case–control studies, have investigated the cancer preventive activity of green tea against different types of cancers. Most of the studies on possible inverse association between green tea consumption and cancer risk have been conducted in Asian countries such as Japan and China, where green tea is widely consumed. Based on the quality of these studies as assessed by several systematic analyses (Liu et al. 2008; Zhou et al. 2008; Boehm et al. 2009; Myung et al. 2009; Sasazuki et al. 2012), we selected 18 cohort and 28 case control studies and compiled a summary in Table 4.1. About half of these studies were focused on cancers in digestive tract, especially gastric cancer.
Among the studies on gastric cancer, the conclusion from the cohort studies except one found no association between gastric cancer risk and green tea consumption. The meta-analyses on the available data conclude that there is no sufficient evidence to support the inverse association (Liu et al. 2008; Zhou et al. 2008; Sasazuki et al. 2012). However, a recent meta-analyses on selected six cohort studies including more than 218,000 Japanese aged 40 or older and over 3,500 incident stomach cancer cases found the statistically significant, inverse association between green tea consumption and stomach cancer risk in nonsmoker women but not in men. A significantly decreased risk was observed for nonsmoker women with consumption of ≥5 cups/day (Inoue et al. 2009).
There are about half of the case–control studies listed in Table 4.1 supporting the inverse association between green tea consumption and gastric cancer risk. Apparently, the studies supporting the inverse association are conducted in China, while the similar studies conducted in Japan do not support the inverse association. Possible error resulted from random events can be ruled out because the sample numbers in all the related studies were sufficient. Inconsistence resulted from the tea composition can also be ruled out because it is generally accepted that the green tea consumed in Japan and China contains the same tea constituents. Perhaps, more details involving the life styles are necessary in order to understand the inconsistence between Chinese and Japanese studies.
The discrepancy can be also found from the studies on the inverse association between green tea consumption and the risk of breast, colorectal, lung, pancreatic, and prostate cancers in Table 4.1. We cannot speculate whether other factors are involved. However, the results from the studies on oral/esophageal and ovarian cancers appear to be consistent. In oral and esophageal cancers, the inverse association has been found in women, but not men in both Japan and China. Results from the two case control studies on leukemia in China are also consistent. Therefore, based on the current data, it is safe to propose that the consumption of green tea can be cancer preventive, but whether it is effective may be related to the etiology of certain cancer.
It should be pointed out again that green tea polyphenols in the subjects of these studies are from the daily consumption and can only reach ~0.1 μM in the blood. The dose of green tea polyphenols found to be effective in animal studies are at a much higher level (>1 μM in the blood). Considering that the bioavailability is a key issue, the intake level of green tea polyphenols should be documented in the future case–control and cohort studies. This can be done by indirectly monitoring the metabolites in urine based on our knowledge about polyphenol metabolism. Such data would be helpful to classify the subjects according to bioavailability levels and to rule out the possible difference in the composition of green tea when similar studies from different area or time are applied for comparison. Given that etiology factors are often related to life-style which could be very different depending on geography or culture, to collect different data for further study such as meta-analysis should involve these records or the related etiology study result. In one example described above, although several meta-analyses found no association between gastric cancer risk and green tea consumption when all studied were combined, the statistically significant inverse association is clear in nonsmoker women (Inoue et al. 2009).
4.2.3 Clinic and Intervention Studies
Limited clinical and intervention studies have been conducted to further explore the application of green tea polyphenols against cancer. In these studies, patients or healthy personals are given the higher doses of green tea polyphenols resulting in the blood levels higher than levels obtained from usual tea consumption. While most results are positive, a clear conclusion in support of anticancer effect cannot be reached. This might due to the fact that the numbers of people in these studies are often very small and the duration of treatment is short compared to that in animal studies. Here, we discuss a few studies in order to understand the opportunity for the application of green tea polyphenols in cancer prevention.
Healthy person can be benefited by the antioxidant activity of green tea polyphenols. Supplementation of green tea polyphenols (500 mg/day) in the diet of healthy persons for 4 weeks reduced oxidized low-density lipoproteins in blood by 18 %, compared to the placebo (Inami et al. 2007). When the similar dose (455 mg/day) was given to patients on haemodialysis for 3 months, plasma hydrogen peroxide, hypochlorous acid, C-reactive protein, and pro-inflammatory cytokines were significantly reduced (Hsu et al. 2007). These results support the concept that green tea polyphenols can improve the antioxidant activity in our body and prevent the damage due oxidative stress.
Some intervention studies provide suggestive evidences for the application of green tea polyphenols against cancer in high risk population. In a double-blind, placebo-controlled study, 60 volunteers with high-grade prostatic intraepithelial neoplasia (HG-PIN) were randomized to receive three capsules (200 mg of green tea polyphenols each; a total of 600 mg/day) or placebo for 1 year. One subject was diagnosed with prostate cancer among 30 men receiving green tea polyphenols (incidence = ~3 %), whereas nine cancers were found among 30 men receiving placebo (incidence = 30 %) (Bettuzzi et al. 2006). The 30 % incident rate in the placebo group was consistent with the clinical data that about 30 % HG-PIN patients develop advanced cancer. This result strongly supports that green tea polyphenols are effective in treating premalignant lesions and preventing its development to advanced tumor. A 2-year follow-up study on a subset of these 60 patients showed a promising protective effect against prostate cancer development (Brausi et al. 2008). In another study on 26 patients receiving green tea polyphenols (1.3 g/day containing 800 mg EGCG) for an average of 35 days during the interval between positive biopsies and radical prostatectomy, the application of green tea polyphenols reduced the levels of cancer-associated biomarkers such as PSA, HGF, VEGF, IGF-1 and IGF-1:IGF binding protein 3 ratio (McLarty et al. 2009). Similarly, in a phase 2 randomized trial consist of 41 patients with high-risk oral premalignant lesions (11 receiving placebo, 11 receiving 500 mg GTE/m2, 9 receiving 750 mg GTE/m2, and 10 receiving 1 g GTE/m2 for 12 weeks), biomarkers such as VEGF and cyclin D1 were significantly reduced in the lesion biopsies (Tsao et al. 2009). This result is consistent with the finding in another randomized, placebo-controlled phase 2 trial that 3 g/day of green tea extract reduced the size of oral mucosa leukoplakia, a precancerous lesion, in 37.9 % patients (Li et al. 1999). In a Japan trial comprised of 136 patients with colorectal adenomas first removed by endoscopic polypectomy and confirmed the clean colon 1 year later (71 receiving with 1.5 g GTE/day for 12 months and 65 as control), the incidence of adenomas at the end-point colonoscopy was 31 % in the control group and 15 % in the GTE group (Shimizu et al. 2008a).
However, there are also studies showing negative results of green tea polyphenols against cancer. An earlier phase 2 trial on 42 patients with hormone-independent prostate cancer showed that receiving green tea polyphenols (a total 6 g/day) for a month increased PSA levels by 43 % (Jatoi et al. 2003). In a recent intervention study randomizing 50 prostate cancer patients scheduled to undergo radical prostatectomy, patients receiving 800 mg EGCG for 3–6 weeks before surgery show favorable when compared to placebo but not statistically significant changes in PSA, IGF, and oxidative DNA damage (Nguyen et al. 2012).
Taken together, the available clinical studies support the cancer preventive activity of green tea polyphenols, but these studies are rather preliminary since the size of the trials is small and the long-term effect is unknown. Albeit, green tea supplement already became the most commonly used product for self-treating breast cancer survivors in Canada (Boon et al. 2007). Now, various green tea products are available over counter and self-treatment may run ahead of our knowledge. The opportunity is on the horizon, but the challenge is how to better design and conduct further clinical study to clearly address whether green tea polyphenols are applicable against cancer. A larger-scale study such as phase 3 trial is necessary to determine the efficacy. Given the fact that we know more about the metabolism of green tea polyphenols, the intake level should be monitored by examining the urine samples frequently. More, future clinical study should integrate the experimental study to apply biomarkers to determine the short-term responsiveness in addition to long-term effect. Furthermore, we suggest to preserve blood, urine, and tissue samples for “-omic” studies. The genomic and proteomic studies using these materials will provide data for understanding the molecular mechanism in-depth. These materials will also be useful to better categorize cancers by the genetic or epigenetic features, the so-called molecular pathological characteristics. Although personalized medicine has not been established in this field, the responsiveness could be possibly associated to specific subtype of cancer if the “-omic” data is available. Based on our knowledge from experimental studies, it is anticipated that a well-designed phase 3 clinical study could determine the efficacy of green tea polyphenols in cancer prevention and clarify whether its application depends on the types or stages of cancer.
4.3 Mechanisms of Tea Polyphenols in Cancer Prevention
To better understand the cancer preventive activity of green tea polyphenols found in animal studies and to promote them for human cancer prevention, substantial studies have been conducted to uncover the mechanism at the cellular and molecular levels. Experimental results collectively show that the treatment of animal cancer models or cancer cells in vitro with green tea polyphenols leads to wide range of responses. It has been reported that green tea polyphenols enhance detoxification to prevent the carcinogen-induced genetic and epigenetic damage (Na and Surh 2006, 2008; Chow et al. 2007), alter epigenetic modification on chromosome such as reducing DNA hypermethylation-associated tumor suppressor silence (Fang et al. 2003; Navarro-Peran et al. 2005; Gao et al. 2009; Choudhury et al. 2011; Nandakumar et al. 2011; Wong et al. 2011), inhibit tumor cell growth by inducing cell cycle arrest and apoptosis (Yang et al. 2009b; Singh et al. 2011), decrease inflammation (Hong et al. 2001; Na and Surh 2006; Pan et al. 2011), and inhibit tumor-associated angiogenesis (Noonan et al. 2007; Yang et al. 2009b; Singh et al. 2011). These activities are consequences of the direct scavenge of ROS and the physical interactions on proteins with various functions. The cancer preventive activity could be resulted from a combinatory effects on multiple targets. The actions of green tea polyphenols mediated through different mechanisms directly lead to the inhibitions on several aspects in carcinogenesis (Fig. 4.3). These aspects are part of the key elements promoting human cancer and also referred to as cancer hallmarks (Hanahan and Weinberg 2011). Compared with the inhibitors designed for targeting specific hallmarks, green tea polyphenols are not potent inhibitors. But, perhaps, it is the inhibitions on multiple hallmarks that lead to the overall anticancer activity of green tea polyphenols albeit most of these inhibitory actions are weak (Fig. 4.3). It is also possible that a specific event/hallmark targeted by EGCG plays dominant role in a specific cancer. To associate any cellular and molecular mechanism to the anticancer activity of EGCG and its application should be carefully evaluated by its effective concentration at the levels compatible to the achievable blood levels in human. In the following, we will discuss the mechanism generally accepted in this field.
4.3.1 Antioxidant Activity
Green tea polyphenols are very sensitive to oxidation reaction. For decades, the antioxidant activity is believed to be the major biological activity of tea polyphenols (Yang et al. 2009a, b; Singh et al. 2011). For example, supplementation of green tea polyphenols (500 mg/day) in diet for healthy individuals for 4 weeks reduces oxidized low-density lipoproteins in blood by 18 % (Inami et al. 2007). In the experimental model, administration of EGCG to aging rats decreases the aging associated oxidative stress and lipid and protein damages (Senthil Kumaran et al. 2008; Srividhya et al. 2008). The similar effect could also protect cells from oxidative DNA damage. It has been reported that the supplement of four cups of green tea with 73.5 mg polyphenols to heavy smokers for 4 months reduced the urinary level of 8-hydroxydeoxy-2′-deoxyguanosine (8-OHdG) by 31 % (Schwartz et al. 2005).
In addition, the indirect antioxidant mechanism, which includes the induction of antioxidant enzymes (i.e. catalase, SOD, etc.) and phase 2 conjugating enzymes (i.e. glutathione-S-transferases, glucuronidase, and sulphotransferases), has been proposed for green tea polyphenols (Na and Surh 2008). In a trial with 42 volunteers receiving green tea extract containing 800 mg/day for 4 weeks, glutathione-S-transferases activity and glutathione-S-transferases-pi (GSTP1) level in blood lymphocytes were increased significantly in individuals with low baseline enzyme activity/level (Chow et al. 2007). Since some of these enzymes are regulated by transcriptional regulator Nrf2, which is responsive to cellular reactive oxygen level, it has been suggested that EGCG enhances Nrf2 activity (Na and Surh 2008). However, this issue remains to be further clarified. EGCG generates ROS via auto-oxidation reaction, as discussed above (Fig. 4.2). It is possible that Nrf2 as the ROS sensor is activated by ROS generated by EGCG. In fact, we have found Nrf2 activity is upregulated in lung cancer cell H1299 carrying Nrf2 binding site-luciferase reporter treated by EGCG, but such an upregulation is abolished when catalase and SOD are added to culture medium. Therefore, it is unlikely that the antioxidant activity of green tea polyphenols involves Nrf2. Whether the indirect antioxidant mechanism is activated through other mechanism remains to be determined.
4.3.2 Direct Binding to Proteins
One major mechanism of the cancer preventive activity of green tea polyphenols is attributed to binding to proteins. Phenolic groups, for example in EGCG, offer hydrogen bond donor to mediate interactions with other molecules. To date, EGCG has been demonstrated to bind physically to a panel of proteins with different affinities. These proteins are featured with varieties of functions involved in cellular signaling, proliferation, apoptosis, structure, and etc. (Singh et al. 2011; Yang and Wang 2011). They underline the involvement of multiple mechanisms, but make it hard to recognize the important one. Sometime, high concentration of EGCG (i.e. ~100 μM) is needed to validate the influence of polyphenols on the functions of these proteins in cells. Such high concentrations raise questions about the physiological relevance of these targets. Indeed, to what degree the binding proteins contributing to the in vivo anticancer activity remains to be determined. Here, we briefly review the proteins with the high-affinity binding EGCG.
Using EGCG-sepharose 4B column, Dong and colleagues have identified a group of proteins that include intermediate filament vimentin, non-receptor tyrosine kinases Fyn and ZAP70, cell signaling regulators GRP78, and Ras-GTPase-activating protein SH3 domain-binding protein 1 (Ermakova et al. 2005, 2006; He et al. 2008; Shim et al. 2008, 2010). Since the binding affinities for these proteins range from 3.3 to 0.7 μM, they are generally considered as the high-affinity binding proteins. Among them, EGCG binds vimentin with Kd = 3.3 nM. However, the role of EGCG binding remains unclear since there is no phenotypic change found in mice with vimentin null mutation (Colucci-Guyon et al. 1994). EGCG binding to Fyn and ZAP70 results in the loss of kinase activity of Fyn and ZAP70. But the inhibition of Fyn and ZAP70 are unlikely to directly mediate the cancer preventive activity of EGCG because these two protein kinases are hematopoietic-cell specific. On the other hand, SH2 domains of Fyn and ZAP70 are the physical binding sites for EGCG, suggesting that EGCG may target other SH2 domain proteins expressed in cancer cells, a possibility that should be explored further. EGCG was also reported to bind and inhibit IGF-1R but with Kd = 14 μM (Li et al. 2007). Although the Kd is higher, it is consistent with the findings of IGF signaling inhibition by EGCG administrated in a colon carcinogenesis model (Shimizu et al. 2008b) and a liver carcinogenesis (Shimizu et al. 2011) in db/db mice and a prostate carcinogenesis in TRAMP mice (Gupta et al. 2001). Thus, both in vitro and in vivo experimental studies support that IGF signaling is an EGCG target.
A recent important finding is the interaction of EGCG with peptidyl prolyl cis/trans isomerase (Pin1). Dong and colleagues demonstrated the physical interaction by X-ray crystal structure of EGCG-Pin1 complex at 1.9 Å resolution (Urusova et al. 2011). This interaction inhibits isomerase activity of Pin1 by preventing the access of its catalytic domain to the substrates (Urusova et al. 2011). Since NF-κB and the AP-1 member c-Jun are Pin1 substrates, this result suggests how EGCG indirectly regulates AP-1 and NF-κB activities, which are critical regulators in both cancer and inflammatory cells. Furthermore, this mechanism is demonstrated to be the mechanism, at least partially, for EGCG to inhibit the growth of colon cancer cells in a xenograft model (Urusova et al. 2011).
Another new finding revealed recently is that EGCG binds and stabilizes HIF-1α and upregulates miR-210 expression (Wang et al. 2011). There are several studies on the regulation of EGCG on HIF-1α but whether EGCG downregulates or upregulates HIF-1α activity remains controversial. By microRNA expression profile analysis of lung cancer cells treated by EGCG, miR-210 is found to be the only microRNA upregulated by EGCG treatment (Wang et al. 2011). Further study reveals that EGCG is likely to bind the key Proline residues in the oxygen-dependent regulatory domain of HIF-1α and prevent the modification of Proline and subsequent proteasome-mediated degradation. Since miR-210 displays suppressor activity in tumor initiation, presumably by regulating the expressions of more than 50 genes (Huang et al. 2009), the upregulation of miR-210 provides an additional mechanism for EGCG to target multiple genes indirectly. However, whether this is the case in vivo needs to be further investigated in the animal model.
Besides the above mentioned targets, EGCG has been reported to bind other proteins and affect their functions. Some of them, such as 67-LR, glucose-6-phosphate dehydrogenase and HGF receptor/c-met, also provide the mechanism for EGCG to interfere with the cellular signaling, metabolism, and inflammatory regulation (Yang and Wang 2011). In addition, EGCG is found to alter plasma membrane through affecting the protein distribution and function in lipid raft, resulting in indirect influence on the activity of EGFR (Adachi et al. 2007), c-Met (Duhon et al. 2010), and 67-LR (Fujimura et al. 2005) at relatively lower concentrations in different cancer cell lines. Therefore, EGCG can display activities on different pathways through these proteins. A combinatory effect of these activities may lead to inhibition of cancer initiation, progression or metastasis (Pan et al. 2011; Singh et al. 2011; Yang and Wang 2011).
4.3.3 Induction of Cell Cycle Arrest and Apoptosis
The anticancer activity resulted from the treatment of green tea polyphenols has been found to be associated to the reduced cell proliferation and increased apoptosis (Yang et al. 2009b; Singh et al. 2011). For example, in the mouse lung cancer models, treatment of green tea polyphenols leads to the significantly reduction of cell proliferation marker Ki-67, pro-proliferation signaling such as the phosphorylation of Akt and ERK1/2, and the increase of cleaved caspase-3, an apoptosis index (Lu et al. 2006a; Li et al. 2010). In various cancer cells cultured in vitro, EGCG has been reported to trigger cell cycle arrest by modulating the levels of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1, and p27/KIP1 as well as p53, and induce apoptosis by increasing levels of pro-apoptotic regulators, Bax, Bak, Bcl-XS, and PUMA, and decreasing levels of anti-apoptotic regulators, Bcl-2 and Bcl-XL (Yang et al. 2009b; Singh et al. 2011). Cell cycle arrest and induction of apoptosis are likely to be resulted from the actions of green tea polyphenols on the targets such as the inhibition on the activities of NF-κB, Ap-1 transcriptional factors, Akt and MAP kinases (Yang et al. 2009b). More, they could be combinatory effects resulted from multiple upstream events targeted by green tea polyphenols.
4.3.4 Anti-angiogenesis
The anticancer activity of green tea polyphenols also involves the inhibition on the growth of tumor-associated blood vessels. Such an anti-angiogenesis activity has been reported to be mediated by the downregulation of VEGF in cancer cells or by direct inhibition on endothelial cells. When cancer cell lines (HeLa, HepG2, and SW837) were treated with EGCG, the hypoxia-induced stabilization of HIF-1α and upregulated expression of VEGF were reduced (Zhang et al. 2006; Shimizu et al. 2010). However, these data are controversial to the results supporting that EGCG can direct bind and stabilize HIF-1α (Thomas and Kim 2005; Weinreb et al. 2007; Wang et al. 2011). Our expression profiles on the EGCG-treated lung cancer H460 cells also show that treatment with EGCG upregulates VEGF and other HIF-1α targets (unpublished data). Thus the anti-angiogenesis via the downregulation of VEGF by EGCG may depend on the cells or cell culture conditions. When endothelial cells such as HUVECs were treated with EGCG, the activity of FOXO was upregulated, resulting in the reduced HUVEC migration and capillary tube formation (Shankar et al. 2008), suggesting the direct inhibitory activity of EGCG on endothelial cells. This result is consistent with the finding that EGCG enhances the phosphorylation and phosphorylation-dependent transcriptional activity of FOXO at lower concentration (i.e. 1 μM) (Anton et al. 2007; Bartholome et al. 2010). Thus, the anticancer activity of green tea polyphenols in animal models involves the anti-angiogenesis via directly modulating the activity of FOXO in endothelial cells.
4.3.5 Other Potential Mechanisms
In addition to above discussed mechanisms, experimental results suggest the involvement of other mechanisms such as anti-inflammation and anti-metastasis. The inhibition on NF-κB and AP-1 transcriptional factors supports that green tea polyphenols play regulatory roles in inflammatory response (Singh et al. 2011). For example, EGCG reduces the virus-induced inflammation mediated through quenching the RONS which activates NF-κB (Lee et al. 2004). Inhibitions on AP-1 transcriptional factors are the downstream events of the inhibition on PI3K/Akt and MAP kinases (Singh et al. 2011). More, as discussed above, the negative regulation on NF-κB and AP-1 factors could be mediated through the inhibition on Pin1 by EGCG (Urusova et al. 2011). Green tea polyphenols are also reported to be effective on inhibiting tumor metastasis in the mouse model using Lewis lung carcinoma cells, which mimic lung metastasis after injected through tail veins. The total number of tumor colonies in lung, an index of metastatic Lewis lung carcinoma cells, has been found reduced significantly by oral administration of green tea polyphenols (Sazuka et al. 1995). In an in vitro assay to measure the metastasis potentials of cancer cells, treatment with EGCG reduces the invasive characteristics of B16 melanoma cells (Watanabe et al. 2012), which might be associated to the reduced matrix metalloproteinases in cancer cells after EGCG treatment (Deng and Lin 2011). In addition to these mechanisms discussed, it can be expected that further in-depth studies on each of these specific directions will uncover more details of the action of green tea polyphenols in cancer prevention. Nevertheless, experimental results support that the anticancer activity of green tea polyphenols is mediated through multiple mechanisms.
4.4 Prospective
In summary, preclinical studies using animal models, molecular and cellular approaches demonstrate the anticancer activities of green tea polyphenols. In addition, limited clinical studies support the cancer preventive effect, despite the mixed results yielded from epidemiology studies. Our understanding of the roles of green tea polyphenols remains incomplete. Further clinical study should integrate new advancements and technologies to systematically monitor the intake, blood and urine levels of green tea polyphenols and metabolites in subjects as well as to determine the short-term responsiveness with biomarkers and correlate it to disease causes, progression, and other aspects. Since the “-omic” technologies are ready for better characterization of individual case based on its genetic and epigenetic background, the tissue sample should be ensured and properly preserved for future extraction of DNA/RNA/protein for -omic analyses.
Furthermore, the combination of green tea polyphenols with other agents or medicines also provides an opportunity to explore the potentials for more effective prevention or treatment. In NNK-induced A/J mouse lung carcinogenesis model, green tea polyphenols display significant inhibition on adenoma progression to adenocarcinoma but not on the induction of adenoma (Lu et al. 2006a). When 0.25 % green tea polyphenols was used with 200 ppm atorvastatin (trade name Lipitor) to treat NNK-induced A/J mouse, the tumor multiplicity was reduced by 56 % and the tumor burden was reduced by 55 % at 20 weeks after NNK-treatment (Lu et al. 2008). When 0.25 % GTE or 200 ppm atorvastatin was used alone, there was no effect significant effect on tumor multiplicity at this stage. Higher dose, 0.5 % GTE or 400 ppm atorvastatin, reduced the tumor burden by 22 % compared with the NNK control group, but no effect on tumor multiplicity (Lu et al. 2008). This work strongly suggests the synergistic effect of polyphenols and atorvastatin on cancer prevention. Other preclinical studies support the synergy of EGCG with other agents, such as taxane (Stearns and Wang 2011), curcumin (Yunos et al. 2011), COX-2 inhibitors (Suganuma et al. 2011), doxorubicin (Stearns et al. 2010), luteolin (Amin et al. 2010), erlotinib (Amin et al. 2009), and sulforaphane (Nair et al. 2008). An exciting advance reported recently is that the combination of EGCG with phosphodiesterase 5 inhibitor (i.e. Vardenafil) significantly potentiates the EGCG induced apoptosis of cancer cells expressing high level of 67-LR (Kumazoe et al. 2013). Low dose of EGCG (i.e. 1 μM) which can be reached in plasma is effective to induce cancer cell death in animal model when administrated with Vardenafil. These combinations effectively inhibit tumor growth in animal model or cancer cell in vitro presumably by targeting different aspects of tumor simultaneously, multiple components in one pathways, or same protein through different mechanisms. Such applications show advantages to overcome several limitations of one agent, which is consistent with the concept to treat cancer with multiple agents to improve the effectiveness, to reduce the side effect or toxicity, and to reduce the possibility of drug resistance (Glickman and Sawyers 2012). For example, the synergistic effect of EGCG and taxane can reduce the toxicity of taxane by using lower dose of taxane (Stearns and Wang 2011). More, the combination of EGCG and erlotinib could be more potent in inhibiting lung cancer with EGFR mutations but also make drug resistance resulted from addition EGFR mutation much less possible by simultaneously targeting EGFR with different mechanisms (Amin et al. 2009). These findings will need to be further investigated to uncover the mechanisms and be validated in both animal and clinical studies. Nevertheless, it opens a new page for the potential application of green tea polyphenols against cancer.
References
Adachi S, Nagao T, Ingolfsson HI, Maxfield FR, Andersen OS, Kopelovich L et al (2007) The inhibitory effect of (−)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. Cancer Res 67:6493–6501
Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H (2004) Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res 64:8715–8722
Amin AR, Khuri FR, Chen ZG, Shin DM (2009) Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and epigallocatechin-3-gallate: the role of p53-dependent inhibition of nuclear factor-kappaB. Cancer Prev Res (Phila) 2:538–545
Amin AR, Wang D, Zhang H, Peng S, Shin HJ, Brandes JC et al (2010) Enhanced anti-tumor activity by the combination of the natural compounds – epigallocatechin-3-gallate and luteolin: potential role of p53. J Biol Chem 285:34557–34565
Anton S, Melville L, Rena G (2007) Epigallocatechin gallate EGCG mimics insulin action on the transcription factor FOXO1a and elicits cellular responses in the presence and absence of insulin. Cell Signal 19:378–383
Balentine DA, Wiseman SA, Bouwens LC (1997) The chemistry of tea flavonoids. Crit Rev Food Sci Nutr 37:693–704
Bartholome A, Kampkotter A, Tanner S, Sies H, Klotz LO (2010) Epigallocatechin gallate-induced modulation of FoxO signaling in mammalian cells and C. elegans: FoxO stimulation is masked via PI3K/Akt activation by hydrogen peroxide formed in cell culture. Arch Biochem Biophys 501:58–64
Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 66:1234–1240
Boehm K, Borrelli F, Ernst E, Habacher G, Hung SK, Milazzo S et al (2009) Green tea Camellia sinensis for the prevention of cancer. Cochrane Database Syst Rev 8:CD005004
Bonner MR, Rothman N, Mumford JL, He X, Shen M, Welch R et al (2005) Green tea consumption, genetic susceptibility, PAH-rich smoky coal, and the risk of lung cancer. Mutat Res 582:53–60
Boon HS, Olatunde F, Zick SM (2007) Trends in complementary/alternative medicine use by breast cancer survivors: comparing survey data from 1998 and 2005. BMC Womens Health 7:4
Brausi M, Rizzi F, Bettuzzi S (2008) Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 54:472–473
Caporali A, Davalli P, Astancolle S, D’Arca D, Brausi M, Bettuzzi S et al (2004) The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis 25:2217–2224
Choudhury SR, Balasubramanian S, Chew YC, Han B, Marquez VE, Eckert RL (2011) (−)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells. Carcinogenesis 32:1525–1532
Chow HH, Cai Y, Alberts DS, Hakim I, Dorr R, Shahi F et al (2001) Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 10:53–58
Chow HH, Hakim IA, Vining DR, Crowell JA, Tome ME, Ranger-Moore J et al (2007) Modulation of human glutathione s-transferases by polyphenon e intervention. Cancer Epidemiol Biomarkers Prev 16:1662–1666
Colucci-Guyon E, Portier MM, Dunia I, Paulin D, Pournin S, Babinet C (1994) Mice lacking vimentin develop and reproduce without an obvious phenotype. Cell 79:679–694
Conney AH, Zhou S, Lee MJ, Xie JG, Yang CS, Lou YR et al (2007) Stimulatory effect of oral administration of tea, coffee or caffeine on UVB-induced apoptosis in the epidermis of SKH-1 mice. Toxicol Appl Pharmacol 224:209–213
Deng YT, Lin JK (2011) EGCG inhibits the invasion of highly invasive CL1-5 lung cancer cells through suppressing MMP-2 expression via JNK signaling and induces G2/M arrest. J Agric Food Chem 59:13318–13327
Duhon D, Bigelow RL, Coleman DT, Steffan JJ, Yu C, Langston W et al (2010) The polyphenol epigallocatechin-3-gallate affects lipid rafts to block activation of the c-Met receptor in prostate cancer cells. Mol Carcinog 49:739–749
Ermakova S, Choi BY, Choi HS, Kang BS, Bode AM, Dong Z (2005) The intermediate filament protein vimentin is a new target for epigallocatechin gallate. J Biol Chem 280:16882–16890
Ermakova SP, Kang BS, Choi BY, Choi HS, Schuster TF, Ma WY et al (2006) (−)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res 66:9260–9269
Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H et al (2003) Tea polyphenol (−)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 63:7563–7570
Feng WY (2006) Metabolism of green tea catechins: an overview. Curr Drug Metab 7:755–809
Fujimura Y, Yamada K, Tachibana H (2005) A lipid raft-associated 67 kDa laminin receptor mediates suppressive effect of epigallocatechin-3-O-gallate on FcepsilonRI expression. Biochem Biophys Res Commun 336:674–681
Fujino Y, Tamakoshi A, Ohno Y, Mizoue T, Tokui N, Yoshimura T (2002) Prospective study of educational background and stomach cancer in Japan. Prev Med 35:121–127
Galanis DJ, Kolonel LN, Lee J, Nomura A (1998) Intakes of selected foods and beverages and the incidence of gastric cancer among the Japanese residents of Hawaii: a prospective study. Int J Epidemiol 27:173–180
Gao YT, McLaughlin JK, Blot WJ, Ji BT, Dai Q, Fraumeni JF Jr (1994) Reduced risk of esophageal cancer associated with green tea consumption. J Natl Cancer Inst 86:855–858
Gao Z, Xu Z, Hung MS, Lin YC, Wang T, Gong M et al (2009) Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res 29:2025–2030
Glickman MS, Sawyers CL (2012) Converting cancer therapies into cures: lessons from infectious diseases. Cell 148:1089–1098
Goto R, Masuoka H, Yoshida K, Mori M, Miyake H (1990) [A case control study of cancer of the pancreas]. Gan No Rinsho Spec No:344–350
Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H (2001) Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci USA 98:10350–10355
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Hao X, Sun Y, Yang CS, Bose M, Lambert JD, Ju J et al (2007) Inhibition of intestinal tumorigenesis in Apcmin/+ mice by green tea polyphenols polyphenon E and individual catechins. Nutr Cancer 59:62–69
He Z, Tang F, Ermakova S, Li M, Zhao Q, Cho YY et al (2008) Fyn is a novel target of (−)-epigallocatechin gallate in the inhibition of JB6 Cl41 cell transformation. Mol Carcinog 47:172–183
Higdon JV, Frei B (2003) Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43:89–143
Hoffmann D, Rivenson A, Hecht SS (1996) The biological significance of tobacco-specific N-nitrosamines: smoking and adenocarcinoma of the lung. Crit Rev Toxicol 26:199–211
Hong J, Smith TJ, Ho CT, August DA, Yang CS (2001) Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem Pharmacol 62:1175–1183
Hoshiyama Y, Kawaguchi T, Miura Y, Mizoue T, Tokui N, Yatsuya H et al (2002) A prospective study of stomach cancer death in relation to green tea consumption in Japan. Br J Cancer 87:309–313
Hou Z, Sang S, You H, Lee MJ, Hong J, Chin KV et al (2005) Mechanism of action of (−)-epigallocatechin-3-gallate: auto-oxidation-dependent inactivation of epidermal growth factor receptor and direct effects on growth inhibition in human esophageal cancer KYSE 150 cells. Cancer Res 65:8049–8056
Hsu SP, Wu MS, Yang CC, Huang KC, Liou SY, Hsu SM et al (2007) Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am J Clin Nutr 86:1539–1547
Huang X, Tajima K, Hamajima N, Inoue M, Takezaki T, Kuroishi T et al (1999) Effect of life styles on the risk of subsite-specific gastric cancer in those with and without family history. J Epidemiol 9:40–45
Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK et al (2009) Hypoxia-inducible miR-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 35:856–867
Ide R, Fujino Y, Hoshiyama Y, Mizoue T, Kubo T, Pham TM et al (2007) A prospective study of green tea consumption and oral cancer incidence in Japan. Ann Epidemiol 17:821–826
Inami S, Takano M, Yamamoto M, Murakami D, Tajika K, Yodogawa K et al (2007) Tea catechin consumption reduces circulating oxidized low-density lipoprotein. Int Heart J 48:725–732
Inoue M, Tajima K, Hirose K, Kuroishi T, Gao CM, Kitoh T (1994) Life-style and subsite of gastric cancer – joint effect of smoking and drinking habits. Int J Cancer 56:494–499
Inoue M, Tajima K, Hirose K, Hamajima N, Takezaki T, Kuroishi T et al (1998) Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan. Cancer Causes Control 9:209–216
Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC (2008) Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis 29:1967–1972
Inoue M, Sasazuki S, Wakai K, Suzuki T, Matsuo K, Shimazu T et al (2009) Green tea consumption and gastric cancer in Japanese: a pooled analysis of six cohort studies. Gut 58:1323–1332
Ishikawa A, Kuriyama S, Tsubono Y, Fukao A, Takahashi H, Tachiya H et al (2006) Smoking, alcohol drinking, green tea consumption and the risk of esophageal cancer in Japanese men. J Epidemiol 16:185–192
Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P et al (2003) A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 97:1442–1446
Ji BT, Chow WH, Yang G, McLaughlin JK, Gao RN, Zheng W et al (1996) The influence of cigarette smoking, alcohol, and green tea consumption on the risk of carcinoma of the cardia and distal stomach in Shanghai, China. Cancer 77:2449–2457
Ji BT, Chow WH, Hsing AW, McLaughlin JK, Dai Q, Gao YT et al (1997) Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 70:255–258
Jian L, Xie LP, Lee AH, Binns CW (2004) Protective effect of green tea against prostate cancer: a case-control study in southeast China. Int J Cancer 108:130–135
Ju J, Liu Y, Hong J, Huang MT, Conney AH, Yang CS (2003) Effects of green tea and high-fat diet on arachidonic acid metabolism and aberrant crypt foci formation in an azoxymethane-induced colon carcinogenesis mouse model. Nutr Cancer 46:172–178
Ju J, Hong J, Zhou JN, Pan Z, Bose M, Liao J et al (2005) Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (−)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Res 65:10623–10631
Ju J, Lu G, Lambert JD, Yang CS (2007) Inhibition of carcinogenesis by tea constituents. Semin Cancer Biol 17:395–402
Kato I, Tominaga S, Matsuura A, Yoshii Y, Shirai M, Kobayashi S (1990) A comparative case-control study of colorectal cancer and adenoma. Jpn J Cancer Res 81:1101–1108
Kato I, Tominaga S, Matsumoto K (1992) A prospective study of stomach cancer among a rural Japanese population: a 6-year survey. Jpn J Cancer Res 83:568–575
Key TJ, Sharp GB, Appleby PN, Beral V, Goodman MT, Soda M et al (1999) Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Br J Cancer 81:1248–1256
Kikuchi N, Ohmori K, Shimazu T, Nakaya N, Kuriyama S, Nishino Y et al (2006) No association between green tea and prostate cancer risk in Japanese men: the Ohsaki Cohort Study. Br J Cancer 95:371–373
Koizumi Y, Tsubono Y, Nakaya N, Nishino Y, Shibuya D, Matsuoka H et al (2003) No association between green tea and the risk of gastric cancer: pooled analysis of two prospective studies in Japan. Cancer Epidemiol Biomarkers Prev 12:472–473
Kono S, Ikeda M, Tokudome S, Kuratsune M (1988) A case-control study of gastric cancer and diet in northern Kyushu, Japan. Jpn J Cancer Res 79:1067–1074
Kumazoe M, Sugihara K, Tsukamoto S, Huang Y, Tsurudome Y, Suzuki T et al (2013) 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. J Clin Invest 123:787–799
Kuo YC, Yu CL, Liu CY, Wang SF, Pan PC, Wu MT et al (2009) A population-based, case-control study of green tea consumption and leukemia risk in southwestern Taiwan. Cancer Causes Control 20:57–65
Kurahashi N, Sasazuki S, Iwasaki M, Inoue M, Tsugane S (2008) Green tea consumption and prostate cancer risk in Japanese men: a prospective study. Am J Epidemiol 167:71–77
Lambert JD, Elias RJ (2010) The antioxidant and pro-oxidant activities of green tea polyphenols: a role in cancer prevention. Arch Biochem Biophys 501:65–72
Lambert JD, Hong J, Yang GY, Liao J, Yang CS (2005a) Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am J Clin Nutr 81:284S–291S
Lambert JD, Rice JE, Hong J, Hou Z, Yang CS (2005b) Synthesis and biological activity of the tea catechin metabolites, M4 and M6 and their methoxy-derivatives. Bioorg Med Chem Lett 15:873–876
Lambert JD, Sang S, Hong J, Kwon SJ, Lee MJ, Ho CT et al (2006) Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate. Drug Metab Dispos 34:2111–2116
Lambert JD, Sang S, Yang CS (2007) Biotransformation of green tea polyphenols and the biological activities of those metabolites. Mol Pharm 4:819–825
Lambert JD, Kwon SJ, Ju J, Bose M, Lee MJ, Hong J et al (2008) Effect of genistein on the bioavailability and intestinal cancer chemopreventive activity of (−)-epigallocatechin-3-gallate. Carcinogenesis 29:2019–2024
Lee MJ, Wang ZY, Li H, Chen L, Sun Y, Gobbo S et al (1995) Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol Biomarkers Prev 4:393–399
Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S et al (2002) Pharmacokinetics of tea catechins after ingestion of green tea and (−)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers Prev 11:1025–1032
Lee KM, Yeo M, Choue JS, Jin JH, Park SJ, Cheong JY et al (2004) Protective mechanism of epigallocatechin-3-gallate against Helicobacter pylori-induced gastric epithelial cytotoxicity via the blockage of TLR-4 signaling. Helicobacter 9:632–642
Li N, Sun Z, Han C, Chen J (1999) The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med 220:218–224
Li M, He Z, Ermakova S, Zheng D, Tang F, Cho YY et al (2007) Direct inhibition of insulin-like growth factor-I receptor kinase activity by (−)-epigallocatechin-3-gallate regulates cell transformation. Cancer Epidemiol Biomarkers Prev 16:598–605
Li GX, Chen YK, Hou Z, Xiao H, Jin H, Lu G et al (2010) Pro-oxidative activities and dose–response relationship of (−)-epigallocatechin-3-gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro. Carcinogenesis 31:902–910
Lin Y, Kikuchi S, Tamakoshi A, Yagyu K, Obata Y, Kurosawa M et al (2008) Green tea consumption and the risk of pancreatic cancer in Japanese adults. Pancreas 37:25–30
Liu J, Xing J, Fei Y (2008) Green tea Camellia sinensis and cancer prevention: a systematic review of randomized trials and epidemiological studies. Chin Med 3:12
Lu YP, Lou YR, Lin Y, Shih WJ, Huang MT, Yang CS et al (2001) Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light high-risk mice: relationship to decreased tissue fat. Cancer Res 61:5002–5009
Lu YP, Lou YR, Xie JG, Peng QY, Liao J, Yang CS et al (2002) Topical applications of caffeine or (−)-epigallocatechin gallate EGCG inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice. Proc Natl Acad Sci USA 99:12455–12460
Lu YP, Lou YR, Liao J, Xie JG, Peng QY, Yang CS et al (2005) Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice. Carcinogenesis 26:1465–1472
Lu G, Liao J, Yang G, Reuhl KR, Hao X, Yang CS (2006a) Inhibition of adenoma progression to adenocarcinoma in a 4-methylnitrosamino-1-3-pyridyl-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine. Cancer Res 66:11494–11501
Lu Y, Yao R, Yan Y, Wang Y, Hara Y, Lubet RA et al (2006b) A gene expression signature that can predict green tea exposure and chemopreventive efficacy of lung cancer in mice. Cancer Res 66:1956–1963
Lu G, Xiao H, You H, Lin Y, Jin H, Snagaski B et al (2008) Synergistic inhibition of lung tumorigenesis by a combination of green tea polyphenols and atorvastatin. Clin Cancer Res 14:4981–4988
Luo J, Inoue M, Iwasaki M, Sasazuki S, Otani T, Ye W et al (2007) Green tea and coffee intake and risk of pancreatic cancer in a large-scale, population-based cohort study in Japan JPHC study. Eur J Cancer Prev 16:542–548
McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA (2009) Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res (Phila) 2:673–682
Meng X, Sang S, Zhu N, Lu H, Sheng S, Lee MJ et al (2002) Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats. Chem Res Toxicol 15:1042–1050
Mizuno S, Watanabe S, Nakamura K, Omata M, Oguchi H, Ohashi K et al (1992) A multi-institute case–control study on the risk factors of developing pancreatic cancer. Jpn J Clin Oncol 22:286–291
Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Chen CW et al (2003) A case–control study on drinking green tea and decreasing risk of cancers in the alimentary canal among cigarette smokers and alcohol drinkers. Zhonghua Liu Xing Bing Xue Za Zhi 24:192–195
Myung SK, Bae WK, Oh SM, Kim Y, Ju W, Sung J et al (2009) Green tea consumption and risk of stomach cancer: a meta-analysis of epidemiologic studies. Int J Cancer 124:670–677
Na HK, Surh YJ (2006) Intracellular signaling network as a prime chemopreventive target of (−)-epigallocatechin gallate. Mol Nutr Food Res 50:152–159
Na HK, Surh YJ (2008) Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol 46:1271–1278
Naasani I, Oh-Hashi F, Oh-Hara T, Feng WY, Johnston J, Chan K et al (2003) Blocking telomerase by dietary polyphenols is a major mechanism for limiting the growth of human cancer cells in vitro and in vivo. Cancer Res 63:824–830
Nair S, Hebbar V, Shen G, Gopalakrishnan A, Khor TO, Yu S et al (2008) Synergistic effects of a combination of dietary factors sulforaphane and (−)-epigallocatechin-3-gallate in HT-29 AP-1 human colon carcinoma cells. Pharm Res 25:387–399
Nakagawa H, Hasumi K, Takami M, Aida-Hyugaji S, Woo JT, Nagai K et al (2007) Identification of two biologically crucial hydroxyl groups of (−)-epigallocatechin gallate in osteoclast culture. Biochem Pharmacol 73:34–43
Nandakumar V, Vaid M, Katiyar SK (2011) (−)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis 32:537–544
Navarro-Peran E, Cabezas-Herrera J, Garcia-Canovas F, Durrant MC, Thorneley RN, Rodriguez-Lopez JN (2005) The antifolate activity of tea catechins. Cancer Res 65:2059–2064
Nguyen MM, Ahmann FR, Nagle RB, Hsu CH, Tangrea JA, Parnes HL et al (2012) Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. Cancer Prev Res (Phila) 5:290–298
Noonan DM, Benelli R, Albini A (2007) Angiogenesis and cancer prevention: a vision. Recent Results Cancer Res 174:219–224
Ohishi T, Kishimoto Y, Miura N, Shiota G, Kohri T, Hara Y et al (2002) Synergistic effects of (−)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane. Cancer Lett 177:49–56
Pan MH, Chiou YS, Wang YJ, Ho CT, Lin JK (2011) Multistage carcinogenesis process as molecular targets in cancer chemoprevention by epicatechin-3-gallate. Food Funct 2:101–110
Sang S, Yang I, Buckley B, Ho CT, Yang CS (2007) Autoxidative quinone formation in vitro and metabolite formation in vivo from tea polyphenol (−)-epigallocatechin-3-gallate: studied by real-time mass spectrometry combined with tandem mass ion mapping. Free Radic Biol Med 43:362–371
Sang S, Lambert JD, Ho CT, Yang CS (2011) The chemistry and biotransformation of tea constituents. Pharmacol Res 64:87–99
Sasazuki S, Inoue M, Hanaoka T, Yamamoto S, Sobue T, Tsugane S (2004) Green tea consumption and subsequent risk of gastric cancer by subsite: the JPHC Study. Cancer Causes Control 15:483–491
Sasazuki S, Inoue M, Miura T, Iwasaki M, Tsugane S (2008) Plasma tea polyphenols and gastric cancer risk: a case–control study nested in a large population-based prospective study in Japan. Cancer Epidemiol Biomarkers Prev 17:343–351
Sasazuki S, Tamakoshi A, Matsuo K, Ito H, Wakai K, Nagata C et al (2012) Green tea consumption and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2012:27
Sazuka M, Murakami S, Isemura M, Satoh K, Nukiwa T (1995) Inhibitory effects of green tea infusion on in vitro invasion and in vivo metastasis of mouse lung carcinoma cells. Cancer Lett 98:27–31
Schwartz JL, Baker V, Larios E, Chung FL (2005) Molecular and cellular effects of green tea on oral cells of smokers: a pilot study. Mol Nutr Food Res 49:43–51
Senthil Kumaran V, Arulmathi K, Srividhya R, Kalaiselvi P (2008) Repletion of antioxidant status by EGCG and retardation of oxidative damage induced macromolecular anomalies in aged rats. Exp Gerontol 43:176–183
Setiawan VW, Zhang ZF, Yu GP, Lu QY, Li YL, Lu ML et al (2001) Protective effect of green tea on the risks of chronic gastritis and stomach cancer. Int J Cancer 92:600–604
Shankar S, Chen Q, Srivastava RK (2008) Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor. J Mol Signal 3:7
Shen MM, Abate-Shen C (2010) Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev 24:1967–2000
Shim JH, Choi HS, Pugliese A, Lee SY, Chae JI, Choi BY et al (2008) (−)-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem 283:28370–28379
Shim JH, Su ZY, Chae JI, Kim DJ, Zhu F, Ma WY et al (2010) Epigallocatechin gallate suppresses lung cancer cell growth through Ras-GTPase-activating protein SH3 domain-binding protein 1. Cancer Prev Res (Phila) 3:670–679
Shimizu M, Fukutomi Y, Ninomiya M, Nagura K, Kato T, Araki H et al (2008a) Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev 17:3020–3025
Shimizu M, Shirakami Y, Sakai H, Adachi S, Hata K, Hirose Y et al (2008b) (−)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. Cancer Prev Res (Phila) 1:298–304
Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Kubota M, Adachi S et al (2010) (−)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells. Chem Biol Interact 185:247–252
Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D et al (2011) Preventive effects of (−)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db Mice. Cancer Prev Res (Phila) 4:396–403
Singh BN, Shankar S, Srivastava RK (2011) Green tea catechin, epigallocatechin-3-gallate EGCG: mechanisms, perspectives and clinical applications. Biochem Pharmacol 82:1807–1821
Song YJ, Kristal AR, Wicklund KG, Cushing-Haugen KL, Rossing MA (2008) Coffee, tea, colas, and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 17:712–716
Sonoda T, Nagata Y, Mori M, Miyanaga N, Takashima N, Okumura K et al (2004) A case–control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet. Cancer Sci 95:238–242
Srividhya R, Jyothilakshmi V, Arulmathi K, Senthilkumaran V, Kalaiselvi P (2008) Attenuation of senescence-induced oxidative exacerbations in aged rat brain by (−)-epigallocatechin-3-gallate. Int J Dev Neurosci 26:217–223
Stearns ME, Wang M (2011) Synergistic effects of the green tea extract epigallocatechin-3-gallate and taxane in eradication of malignant human prostate tumors. Transl Oncol 4:147–156
Stearns ME, Amatangelo MD, Varma D, Sell C, Goodyear SM (2010) Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am J Pathol 177:3169–3179
Suganuma M, Saha A, Fujiki H (2011) New cancer treatment strategy using combination of green tea catechins and anticancer drugs. Cancer Sci 102:317–323
Sun CL, Yuan JM, Koh WP, Lee HP, Yu MC (2007) Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study. Carcinogenesis 28:2143–2148
Suzuki Y, Tsubono Y, Nakaya N, Koizumi Y, Tsuji I (2004) Green tea and the risk of breast cancer: pooled analysis of two prospective studies in Japan. Br J Cancer 90:1361–1363
Suzuki Y, Tsubono Y, Nakaya N, Koizumi Y, Shibuya D, Tsuji I (2005) Green tea and the risk of colorectal cancer: pooled analysis of two prospective studies in Japan. J Epidemiol 15:118–124
Tajima K, Tominaga S (1985) Dietary habits and gastro-intestinal cancers: a comparative case–control study of stomach and large intestinal cancers in Nagoya, Japan. Jpn J Cancer Res 76:705–716
Thomas R, Kim MH (2005) Epigallocatechin gallate inhibits HIF-1alpha degradation in prostate cancer cells. Biochem Biophys Res Commun 334:543–548
Tsao AS, Liu D, Martin J, Tang XM, Lee JJ, El-Naggar AK et al (2009) Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila) 2:931–941
Tsubono Y, Nishino Y, Komatsu S, Hsieh CC, Kanemura S, Tsuji I et al (2001) Green tea and the risk of gastric cancer in Japan. N Engl J Med 344:632–636
Urusova DV, Shim JH, Kim DJ, Jung SK, Zykova TA, Carper A et al (2011) Epigallocatechin-gallate suppresses tumorigenesis by directly targeting Pin1. Cancer Prev Res (Phila) 4:1366–1377
Valcic S, Burr JA, Timmermann BN, Liebler DC (2000) Antioxidant chemistry of green tea catechins. New oxidation products of (−)-epigallocatechin gallate and (−)-epigallocatechin from their reactions with peroxyl radicals. Chem Res Toxicol 13:801–810
Vittal R, Selvanayagam ZE, Sun Y, Hong J, Liu F, Chin KV et al (2004) Gene expression changes induced by green tea polyphenol (−)-epigallocatechin-3-gallate in human bronchial epithelial 21BES cells analyzed by DNA microarray. Mol Cancer Ther 3:1091–1099
Wang M, Guo C, Li M (1999) A case–control study on the dietary risk factors of upper digestive tract cancer. Zhonghua Liu Xing Bing Xue Za Zhi 20:95–97
Wang JM, Xu B, Rao JY, Shen HB, Xue HC, Jiang QW (2007) Diet habits, alcohol drinking, tobacco smoking, green tea drinking, and the risk of esophageal squamous cell carcinoma in the Chinese population. Eur J Gastroenterol Hepatol 19:171–176
Wang H, Bian S, Yang CS (2011) Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1alpha. Carcinogenesis 32:1881–1889
Watanabe T, Kuramochi H, Takahashi A, Imai K, Katsuta N, Nakayama T et al (2012) Higher cell stiffness indicating lower metastatic potential in B16 melanoma cell variants and in (−)-epigallocatechin gallate-treated cells. J Cancer Res Clin Oncol 2012:2
Weinreb O, Amit T, Youdim MB (2007) A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (−)-epigallocatechin-3-gallate. Free Radic Biol Med 43:546–556
Weisburger JH (1999) Tea and health: the underlying mechanisms. Proc Soc Exp Biol Med 220:271–275
Weisburger JH (2003) Prevention of coronary heart disease and cancer by tea, a review. Environ Health Prev Med 7:283–288
Wong CP, Nguyen LP, Noh SK, Bray TM, Bruno RS, Ho E (2011) Induction of regulatory T cells by green tea polyphenol EGCG. Immunol Lett 139:7–13
Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC (2003) Green tea and risk of breast cancer in Asian Americans. Int J Cancer 106:574–579
Yang CS, Wang H (2011) Mechanistic issues concerning cancer prevention by tea catechins. Mol Nutr Food Res 55:819–831
Yang CS, Maliakal P, Meng X (2002) Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol 42:25–54
Yang G, Shu XO, Li H, Chow WH, Ji BT, Zhang X et al (2007) Prospective cohort study of green tea consumption and colorectal cancer risk in women. Cancer Epidemiol Biomarkers Prev 16:1219–1223
Yang CS, Lambert JD, Sang S (2009a) Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol 83:11–21
Yang CS, Wang X, Lu G, Picinich SC (2009b) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9:429–439
Yang CS, Wang H, Li GX, Yang Z, Guan F, Jin H (2011) Cancer prevention by tea: evidence from laboratory studies. Pharmacol Res 64:113–122
Ye WM, Yi YN, Luo RX, Zhou TS, Lin RT, Chen GD (1998) Diet and gastric cancer: a casecontrol study in Fujian Province, China. World J Gastroenterol 4:516–518
Yu GP, Hsieh CC, Wang LY, Yu SZ, Li XL, Jin TH (1995) Green-tea consumption and risk of stomach cancer: a population-based case–control study in Shanghai, China. Cancer Causes Control 6:532–538
Yunos NM, Beale P, Yu JQ, Huq F (2011) Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells. Anticancer Res 31:1131–1140
Zhang M, Binns CW, Lee AH (2002) Tea consumption and ovarian cancer risk: a case–control study in China. Cancer Epidemiol Biomarkers Prev 11:713–718
Zhang Q, Tang X, Lu Q, Zhang Z, Rao J, Le AD (2006) Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1alpha protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Mol Cancer Ther 5:1227–1238
Zhang M, Holman CD, Huang JP, Xie X (2007) Green tea and the prevention of breast cancer: a case–control study in Southeast China. Carcinogenesis 28:1074–1078
Zhang M, Zhao X, Zhang X, Holman CD (2008a) Possible protective effect of green tea intake on risk of adult leukaemia. Br J Cancer 98:168–170
Zhang XD, Zhao XY, Zhang M, Liang Y, Xu XH, D’Arcy C et al (2008b) A case–control study on green tea consumption and the risk of adult leukemia. Zhonghua Liu Xing Bing Xue Za Zhi 29:290–293
Zhong L, Goldberg MS, Gao YT, Hanley JA, Parent ME, Jin F (2001) A population-based case–control study of lung cancer and green tea consumption among women living in Shanghai, China. Epidemiology 12:695–700
Zhou Y, Li N, Zhuang W, Liu G, Wu T, Yao X et al (2008) Green tea and gastric cancer risk: meta-analysis of epidemiologic studies. Asia Pac J Clin Nutr 17:159–165
Zhu BT, Patel UK, Cai MX, Conney AH (2000) O-Methylation of tea polyphenols catalyzed by human placental cytosolic catechol-O-methyltransferase. Drug Metab Dispos 28:1024–1030
Acknowledgment
This work was supported by NIH grants CA120915, CA122474, and CA133021.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Wang, H., Zhou, H., Yang, C.S. (2013). Cancer Prevention with Green Tea Polyphenols. In: Cho, W. (eds) Cancer Chemoprevention and Treatment by Diet Therapy. Evidence-based Anticancer Complementary and Alternative Medicine, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6443-9_4
Download citation
DOI: https://doi.org/10.1007/978-94-007-6443-9_4
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-6442-2
Online ISBN: 978-94-007-6443-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)