1.1. Prostate cancer: Opportunity for prevention
Prostate cancer (PCa) is the most commonly diagnosed cancer and second most common cause of cancer deaths in American men. The American Cancer Society estimates that there will be 233,000 new cases of prostate cancer in the United States (US) in 2014, and 29,480 men will die from this disease.  The initiation and progression of PCa involves a complex series of events. During progression, genetic changes and loss of cellular control are observed as cell phenotypes change from normal to dysplasia (prostatic intraepithelial neoplasia or PIN), severe dysplasia (high-grade PIN or HGPIN), atypical small acinar proliferation (ASAP) or focal glandular prostatic atypia (FGA), [2, 3] clinically localized and finally to metastatic disease. [2, 4 - 7] The frequency of HGPIN as well as latent PCa is evenly distributed, suggesting that external factors such as diet, physical activity, and other lifestyle factors are important in the transformation from these early stages into more aggressive, clinical cancer. [2, 4 - 9] Although early screening and detection has been used historically as strategies for PCa prevention, these recommendations have been a subject of much debate in recent years. Although screening using serum prostate-specific antigen (PSA) has not been shown to significantly reduce either PCa-specific or overall mortality, it has been linked to the substantial overtreatment of clinically insignificant, potentially indolent tumors. [10 - 12] With questions about value of prostate-specific antigen (PSA)-based screening, [10 - 12] few prevention options are available for asymptomatic men who are at high risk for PCa. To address the urgent need for alternative preventive strategies, hormonal agents including the 5-alpha-reductase inhibitors finasteride and dutasteride, which block the conversion of testosterone to dihydrotestosterone, have been evaluated for PCA chemoprevention. [13 - 15] Although a reduction in PCa incidence of 23%–25% was observed with these agents, [13, 15] concerns about higher incidence of aggressive cancers and toxicities have limited their clinical adoption, establishing the need to identify alternative chemoprevention agents  with a more favorable safety profile. These features of prostate cancer, namely, high prevalence, long latency, significant mortality and morbidity, availability of HGPIN and ASAP as intermediate predictive stages of progression, and urgent need for alternative strategies for prevention other than screening, provide the most promise and best opportunity for evaluating agents for chemoprevention.
2. Cancer chemoprevention
Chemoprevention refers to the inhibition of preinvasive and invasive cancer and its progression or treatments of identifiable precancers. [16, 17] Successful chemopreventive interventions require a thorough evidence-based understanding of the mechanism and hallmarks of carcinogenesis. Novel technologies, methods, and approaches in genomics, metabolomics, and proteomics have enabled this field of research. In order for chemopreventive efforts to be successful, it is imperative to employ these innovative methods and approaches to develop pharmacologic agents (including botanicals/biologicals) to reverse or halt the process of carcinogenesis. Chemopreventive agents include antipromotion and antiprogression compounds that could prevent or stop the survival, growth, and dissemination/metastasis of cells that are already committed to become malignant. [16, 17]
3. Botanicals as agents for cancer chemoprevention
Although several targeted “smart” drugs have emerged over the past decade, it is clear that diseases like cancer have an etiology based on perturbations of multiple signaling pathways. Thus, targeting multiple pathways may represent a more effective approach to cancer control. [18 - 20] In addition, the monotargeted “smart” drugs are associated with high cost and produce numerous side effects. These drawbacks of monotargeted drugs underscore the importance for the development of multitargeted, innocuous, inexpensive, and readily available botanicals for the prevention of cancer.  Botanicals have been shown to influence multiple biochemical and molecular cascades that inhibit mutagenesis and proliferation, induce apoptosis, and suppress the formation and growth of human cancers, modulating several hallmarks of carcinogenesis, with a significantly superior safety profile than most agents evaluated to date. Multiple botanicals have been identified and appear promising for PCa chemoprevention. 
The objective of this chapter is to review and summarize the most current literature focusing on GTC for prostate cancer chemoprevention based on evidence from laboratory,
4. Green tea catechins and prostate cancer chemoprevention
4.1. Epidemiological evidence of the role of GTC and prostate cancer prevention
Several reviews summarizing epidemiological evidence have suggested a protective effect of tea consumption against human cancers of the breast, cervix, colon and rectum, gallbladder, liver, lung, nasopharynx, pancreas, prostate, stomach, ovary, and uterus. [32 - 35] Twenty percent of green tea is consumed in Asian countries such as China, Japan, and Korea, where populations drinking green tea consistently demonstrate lower PCa risks. Epidemiological studies, however, have been mixed, potentially due to confounding factors such as variations in tea consumption(salted, hot), dietary, tobacco and alcohol use, genetic differences, and recall bias. [36, 50] The risk for PCa increases in Asians who migrate to the US if original dietary habits are abandoned. There is epidemiological evidence that Asian men consuming green tea have lower PCa risk, potentially due to exposure over their lifetime that prevents transformation or progression to later stages of prostate carcinogenesis. The conflicting epidemiological results have been attributed to confounding factors that include consumption of salted or very hot tea, geographical location, use of tobacco and alcohol, other dietary differences, and lack of standardization of quantities and compositions of the tea products consumed. In a case–control study conducted in China during 2001–2002, prostate cancer risk declined with increasing frequency, duration, and quantity of green tea consumption [OR = 0.28 (95% CI = 0.17−0.47)], showing a dose–response relationship.  Four to five times more men die of CaP in the US than that in Japan.  It also appears that the onset of CaP occurs later in life and/or CaPs grow more slowly in Japanese populations compared to Western populations, which may be attributed to the consumption of GTC and soy products. Thus, the potential preventive properties of GTP in prostate cancer, as demonstrated by evidence from epidemiological studies although limited, appear promising.
4.2. Preclinical evidence of the role of GTC and prostate cancer prevention
Several published preclinical studies using green tea, green tea leaves, green tea extracts, GTP mixtures, green tea catechin (GTC) mixtures, and the individual catechins have demonstrated chemopreventive efficacy in several cancers. [51 - 57] Using the TRAMP mice model, Gupta et al.  were able to demonstrate that oral infusion of GTP extract at a human achievable dose (equivalent to six cups of green tea per day) significantly inhibits CaP development and increases survival in these mice. When 0.1% GTP (weight/volume) was provided as the sole source of drinking water to transgenic adenocarcinoma mouse prostate (TRAMP) mice 8–32 weeks of age, the result was (i) substantial reduction in the tumor incidence, tumor burden, and delay in metastasis as assessed by magnetic resonance imaging (MRI); (ii) substantial reduction in prostate (by 64%) and genitourinary (GU) (by 72%) weight; (iii) substantially decreased serum insulin-like growth factor-I (IGF-I) and restored to normal insulin-like growth factor binding protein-3 levels (IGFBP-3); and (iv) marked decrease in the expression of proliferating cell nuclear antigen (PCNA) in the prostate compared with control (water-fed) TRAMP mice. Furthermore, GTP consumption caused significant apoptosis of CaP cells, which possibly resulted in reduced dissemination of cancer cells, thereby causing the inhibition of CaP development, progression, and metastasis of CaP to distant organ sites. However, in another similar animal model, epigallocatechin gallate (EGCG) only slightly reduced these levels.  These observations may be attributed to the pharmacokinetic properties of EGCG, which has relatively low oral bioavailability.  These inconsistencies could also be explained by differential doses, different methods of infusion, duration of intervention, and inadequate timing of castration necessary to observe changes in markers of progression and the antioxidant property of EGCG. Oral administration of GTPs (
4.3. Potential mechanism by which GTC modulates prostate carcinogenesis:
A body of research evidence indicates that tea and tea compounds reduce the growth of several human cancer cell lines
In their recent review of signaling pathways that are affected by green tea polyphenols, Khan et al.  reported that various pathways mediated via mitogen-activated protein kinases (MAPK) signaling were affected, including extracellular-signal-related kinases (ERK1/2), c-Jun N-terminal kinases/stress-activated protein kinases (JNK1/2/3 or SAPKs), p38 MAPK, ERK3/4, ERK5, and ERK7/8. Ultimately, MMP-2 and MMP-9 expressions were affected by EGCG via inhibition of phosphorylation of ERK1/2 and p38 pathways. Since MMP-9 and MMP-2 are known biomarkers of invasion and metastasis, the inhibition of their expression leads to inhibition of prostate cancer spread. Insulin-like growth factors (IGF) exert multiple effects on glucose, fat, and protein metabolism and play important roles in regulating cell proliferation, differentiation, apoptosis, and transformation. PI3K/Akt and Ras/MAPK pathways can be activated via IGF-signaling, supporting cell proliferation. GTCs are known to suppress cellular signaling via the IGF-axis, thus affecting cell proliferation. Cyclooxygenase (COX) is a rate-limiting enzyme in the prostaglandin biosynthesis. COX-2 can be activated via NF-κB signaling pathway, leading to inflammation and cell proliferation. EGCG was shown to inhibit COX-2 expression at both the mRNA and the protein levels in the prostate, thus slowing down the cancer growth. Finally, EGCG have a notable effect on cell cycle arrest. Gupta et al.  have earlier reported that treatment of CaP cell lines LNCaP and DU145 with EGCG caused cell cycle disruptions and reduced proliferation of cells due to down-regulation of various cyclins as well as altered binding to CDKs. Treatment of human CaP cell lines LNCaP and PC-3 with GTP caused the inhibition of class I HDAC activity, leading to cell cycle arrest and induction of apoptosis.
Yang et al.  have recently reported that phenolic groups of EGCG can directly bind to multiple molecules due to their hydrogen bonds. The molecules of interest include B-cell CLL/lymphoma 2 protein (BCL2), which has antiapoptotic properties, leading to induction of apoptosis. Some other EGCG binding targets include glucose-regulated protein 78 kDa, vimentin, IGF-1R, and peptidylcis/trans isomerase. Via this mechanism, EGCG can modulate the formation of reactive oxygen species (ROS) as well as affect other molecular pathways described above.
Rizzi et al.  reported that Poly E induced cell cycle arrest at the G0/G1 checkpoint for PNT1a prostate cell lines (modeling early stage disease) and G2/M for PC3 cells (modeling late stage disease). The authors showed that in the model of an early stage disease, autophagy was the first mechanism to activate in response to endoplasmic reticulum stress (ERS). After that stage, which lasted approximately 12 h, activation of caspases occurred, indicating anoikis cell death. In the model of an aggressive CaP, Poly E induced severe ERS which eventually led to GADD153/CHOP activated Puma, a BH3-only protein, committing cells to necroptosis, a programmed caspase-independent mechanism of cell death. These results may aid in the identification of novel targets and strategies aimed at sensitizing apoptosis-resistant cells to alternative death pathways.
Hagen et al.  reported that EGCG induced apoptosis in PC3 cells, via the caspase 9-dependent mechanism. Furthermore, EGCG, both alone and in combination with cisplatin, promoted the expression of the proapoptotic splice isoform of caspase 9, and it modifies the alternative splicing of caspase 9, favoring the proapoptotic isoform. The latter finding suggests that EGCG may affect the alternative splicing of cancer-associated genes
Connors et al.  have previously proposed a mechanistic model according to which GTCs antitumor action in prostate cancer acts through proteasome. GTC-induced inhibition of chymotrypsin-like activity of the proteasome results in the accumulation proteasome targets p21, p27, Bax, and IκBα. The accumulation of cell cycle regulators p21 and p27 result in G1 cell cycle arrest, whereas the accumulation of the proapoptotic protein, Bax, contributes to cell apoptosis. The oncogenic transcription factor, NFκB, is down-regulated, presumably by the elevation of IκBα, its intrinsic inhibitor. This results in the reduced expression of NFκB target genes, antiapoptotic, Bcl-xL and Bcl-2, cell cycle regulators, cyclin D and cyclin E, and metastasis-related genes, VEGF, angiopoietin 1/2, MMPs, and uPA. Reductions in cyclins D and E, Bcl-2, and Bcl-xL further drive the processes of cell cycle arrest, decreased cell proliferation, and apoptosis, respectively. Additionally, the reduction in metastasis-related genes inhibits tumor cell invasion and metastasis.
Based on their studies of GTP in cell culture systems, Adhami et al.  were able to demonstrate that EGCG in GTP induces apoptosis, cell growth inhibition, and cyclin kinase inhibitor WAF-1/p21-mediated cell cycle dysregulation.Using cDNA microarrays, they also observed that the EGCG treatment of LNCaP cells results in the induction of genes that functionally exhibit growth-inhibitory effects and repression of genes that belong to the G-protein signaling network. When oral feeding of GTP was the sole source of drinking fluid for TRAMP mice, a significant inhibition of VEGF, MMP-2, and MMP-9 was demonstrated, suggesting antimetastatic and antiangiogenic properties of GTP that may affect CaP progression.  Bettuzzi et al. have validated these findings, showing that oral administration of GTP to TRAMP mice reduced CaP onset from 100% to 20%  mediated by induction of clusterin (CLU) expression, which is potently up-regulated during prostate gland involution  but down-regulated in human CaP specimens [73, 74] and exerts antiproliferative  and proapoptotic activity [76 - 79] in PNT1a and PC-3 cells.
EGCG potently and selectively inhibits the proteasome activity in intact human CaP cells and consequently accumulates IkBα and p27 proteins, leading to growth arrest (Figure 1). [59 - 61] ECCG has been shown to decrease NF-κB DNA binding and abrogates NF-κB activation by DNA-damaging agents. Our group also reported that EGCG was able to inhibit NF-κB activation through stabilization of IκBα. [58 - 61] NF-κB is a eukaryotic transcription factor involved in the regulation of COX-2 and many other genes.  The constitutive activation of NF-κB has been reported in many tumors, [80, 81] associating it with progression of epithelial cells, including prostate, toward malignancy. This inhibition of proteasome activity by EGCG occurred at or near physiological concentrations
In summary, there is increasing experimental evidence that GTCs slow down prostate carcinogenesis via an umbrella of mechanisms and cellular pathways that work in concert to affect multiple hallmarks of cancer. The main pathways include proteasome inhibition, cell cycle arrest, inhibition of cell proliferation, induction of apoptosis, suppression of growth and invasion, and inhibition of metastasis. Further research should elucidate the exact sequence of cellular events induced by GTCs that lead to suppression of prostate malignancy.
4.4. Clinical experience: green tea polyphenols and prostate cancer
Several phase I studies, sponsored by the National Cancer Institute’s Division of Cancer Prevention (NCI, DCP) and others, comparing the pharmacokinetics and safety of oral green tea, polyphenon E, and EGCG, have been completed and published. [96 - 99, 100] By conducting a phase I trial of oral green tea extract in adult patients with solid tumors, Pisters et al.  reported that a safe dose of green tea extract was equivalent to 7–8 Japanese cups (120 ml) of green tea three times daily for 6 months. They concluded that the side effects (neurological and gastrointestinal effects) of the green tea extract preparation were caffeine related, and not from EGCG
In a single-dose study sponsored by NCI, DCP, each subject received two single doses containing 200, 400, 600, or 800 mg EGCG provided by each of two different formulations (polyphenon E or a purified EGCG preparation) separated by a 2-week washout period.  Plasma EGCG levels increased with dose and formulation had no effect on EGCG pharmacokinetics. Although little EGCG circulated in conjugated form, EGC and EC were highly conjugated. In a completed multidose study, healthy subjects with sun-sensitive skin received 800 mg EGCG alone or as polyphenon E in one or divided daily doses for 4 weeks.  Adverse effects were predominantly mild gastrointestinal complaints. Plasma levels of EGCG were significantly higher in the 400 mg qd versus 400 mg bid dose group for both formulations. Plasma antioxidant levels and UV light-induced minimum erythema dose (MED) were unaffected by any treatment. In the third completed phase I study, the effect of fasting on pharmacokinetics was examined in healthy adults taking 400, 800, or 1200 mg EGCG as polyphenon E. Plasma levels of free EGCG were dramatically higher when taking polyphenon E in the fasting state compared to the fed state for all three dose levels; the average
Bettuzzi et al. [102 - 103] completed a randomized clinical trial to assess safety and efficacy of GTCs for chemoprevention of CaP in men diagnosed with HGPIN.  Purity and content of GTCs preparations were assessed by HPLC (EGC 5.5%, EC 12.24%, EGCG 51.88%, ECG 6.12%, total GTCs 75.7%, caffeine <1%). After 1-year intervention with GTC tablets containing 600 mg EGCG/day, only one tumor was diagnosed among the 30 GTC-treated men (incidence: about 3%), while nine cancers were found among the 30 placebo-treated men (incidence: 30%). After 9 months of treatment, subjects taking GTC had a 17% decrease in total PSA values; otherwise, PSA values did not change significantly between the two arms of the study, probably because of high individual differences. No significant side effects were documented. As a secondary observation, they found that the administration of GTCs at this dose was also effective at reducing LUTS. However, other studies intervening in men with localized prostate cancer in the presurgical phase (from biopsy to prostatectomy) with GTC failed to observe chemopreventive benefit [104 - 106] observed in trials targeting earlier stages of prostate carcinogenesis (HGPIN). These early trials indicate that GTC may not exert a meaningful effect once diagnosed with prostate cancer and, consistent with earlier preclinical trials, [54, 104] have observed decreasing effectiveness of GTC with advancing stage of PCa using a TRAMP mouse model. In summary, evidence from phase I/II studies has demonstrated bioavailability and tolerance to GTC at doses ranging from 200 to 1200 mg per day and for a duration of 1 year with observation of chemoprevention effects in the early stages (HGPIN) of prostate carcinogenesis and not in the later stages. With few options available for the chemoprevention of early precursors of PCa, GTC shows promise to be further evaluated as chemoprevention agents targeting high-risk cohorts with HGPIN.
5. Conclusions and future directions
GTCs are promising agents for the chemoprevention of prostate cancer. Early observations indicate that GTCs at human achievable doses are most effective against early stage prostate carcinogenesis in preclinical and clinical trials and are attractive chemopreventive agents with a favorable safety profile. There is an urgent need to continue to identify chemopreventive agents to reduce the burden of cancer. However, it is just as critical to learn from the experience of past chemoprevention trials [108 - 115] that underscore the need for systematically characterizing these agents for cancer chemoprevention and defining their efficacy, safety, and mechanism of action using preclinical and early-phase work before undertaking phase III trials and ultimately translating the findings to clinical practice.
American Cancer Society. http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-key-statistics
Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175(3 Pt 1):820–34.
Iczkowski KA. Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains. Arch Pathol Lab Med. 2006;130(6):835–43.
Bostwick DG, Burke HB, Djakiew D, et al. Human prostate cancer risk factors. Cancer. 2004;101(10 Suppl):2371–490.
Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Mod Pathol. 2004;17(3):360–79.
Kelloff GJ, Lieberman R, Steele VE, et al. Chemoprevention of prostate cancer: conceptsand strategies. Eur Urol. 1999;35(5–6):342–50.
Mohamed MA, Greif PA, Diamond J, et al. Epigenetic events, remodelling enzymes and their relationship to chromatin organization in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. BJU Int. 2007;99(4):908–15.
Burzon D, Kahnoski RJ, Bennett JK, Barnette KG, Steiner MS. Men with high-grade prostatic intraepithelial neoplasia (HGPIN) remain at high risk for prostate cancer regardless of whether HGPIN is detected on subsequent biopsies. J Urol. 2005;173(4 Suppl):Abst No. 673.
Lieberman R. Prostate cancer chemoprevention: strategies for designing efficient clinical trials. Urology. 2001;57(4 Suppl 1):224–9.
Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360(13):1310–9.
Ilic D, O’Connor D, Green S, Wilt TJ. Screening for prostate cancer: an updated Cochrane systematic review. BJU Int. 2011;107(6):882–91.
Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120–34.
Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010;362(13):1192–202.
Hamilton RJ, Kahwati LC, Kinsinger LS. Knowledge and use of finasteride for the prevention of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:2164–71.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215–24.
Murtola TJ, Kujala PM, Tammela TL. High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5α-reductase inhibitors and alpha-blockers. Prostate. 2013 Jun;73(9):923–31.
Kelloff GJ, Lippman SM, Dannenberg AJ, et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward. Clin Cancer Res. 2006;12(12):3661–97.
Sung B, Prasad S, Yadav VR, Aggarwal BB. Cancer cell signaling pathways targeted by spice-derived nutraceutials. Nutr Cancer. 2012;64:173–197.
Gupta SC, Prasad S, Kim JH, Patchva S, Webb LJ, Priyadarsini IK, Aggarwal BB. Multitargeting by curcumin as revealed by molecular interaction studies. Nat Prod Rep. 2011;28:1937–55.
Kannappan R, Gupta SC, Kim JH, Aggarwal BB. Tocotrienols fights cancer by targeting multiple cell signaling pathways. Genes Nutr. 2012;7:43–52.
Aravindaram K, Yang NS. Anti-inflammatory plant natural products for cancer therapy. Planta Med. 2010;76(11):1103–17.
Clinton SK. Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev. 1998;56(2 Pt 1):35–51.
Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002;94(5):391–8.
Kakarala M, Brenner DE, Korkaya H, et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010;122(3):777–85.
Kumar NB, Krischer JP, Allen K, et al. A phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. Nutr Cancer. 2007;59(2):163–8.
Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39–51.
Minich DM, Bland JS. A review of the clinical efficacy and safety of cruciferous vegetable phytochemicals. Nutr Rev. 2007;65(6 Pt 1):259–67.
Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst. 1996;88(21):1550–9.
Scott EN, Gescher AJ, Steward WP, Brown K. Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials. Cancer Prev Res (Phila). 2009;2(6):525–30.
Kumar NB, Dhurandhar M, Aggarwal NT, et al. Proceedings of the Indo-U.S. bilateral workshop on accelerating botanicals/biologics agent development research for cancer chemoprevention, treatment, and survival. Cancer Med. 2013;2(1):108–15.
Kumar N, Chornokur G. Molecular targeted therapies using botanicals for prostate cancer chemoprevention. Transl Med (Sunnyvale). 2012;Suppl 2:005.
Kelloff GJ, Crowell JA, Hawk ET, et al. Clinical development plan: tea extracts, green tea polyphenols, epigallocatechin gallate. J Cell Biochem. 1996;26(Suppl):236–57.
Bushman JL. Green tea and cancer in humans: a review of the literature. Nutr Cancer. 1998;31(3):151–9.
Higdon JV, Frei B. Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr. 2003;43(1):89–143.
Ahn WS, Yoo J, Huh SW, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev. 2003;12(5):383–90.
Jian L, Xie LP, Lee AH, Binns CW. Protective effect of green tea against prostate cancer: a case–control study in southeast China. Int J Cancer. 2004;108(1):130–5.
Lee J, Demissie K, Lu SE, Rhoads GG. Cancer incidence among Korean-American immigrants in the United States and native Koreans in South Korea. Cancer Control. 2007;14(1):78–85.
Maskarinec G, Noh JJ. The effect of migration on cancer incidence among Japanese in Hawaii. Ethn Dis. 2004;14(3):431–9.
Nelson WG. Agents in development for prostate cancer prevention. Expert Opin Investig Drugs. 2004;13(12):1541–54.
Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. Green tea and risk of breast cancer in Asian Americans. Int J Cancer. 2003;106(4):574–9.
Borrelli F, Capasso R, Russo A, Ernst E. Systematic review: green tea and gastrointestinal cancer risk. Aliment Pharmacol Ther. 2004;19(5):497–510.
Ito K. Prostate cancer in Asian men. Nat Rev Urol. 2014;11(4):197–212.
Kelloff GJ, Lippman SM, Dannenberg AJ, et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer—a plan to move forward. AACR Task Force on Cancer Prevention. Clin Cancer Res. 2006 Jun 15;12(12):3661–97. Review.
Liang W, Binns CW, Jian L, Lee AH. Does the consumption of green tea reduce the risk of lung cancer among smokers? Evid Based Complement Alternat Med. 2007;4(1):17–22. 17342237.
Lin YW, Hu ZH, Wang X, Mao QQ, Qin J, Zheng XY, Xie LP. Tea consumption and prostate cancer: an updated meta-analysis. World J Surg Oncol. 2014;12:38.
Sun CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis. 2006;27(7):1310–5.
Woolcott CG, King WD, Marrett LD. Coffee and tea consumption and cancers of the bladder, colon and rectum. Eur J Cancer Prev. 2002;11(2):137–45.
Yuan JM. Cancer prevention by green tea: evidence from epidemiologic studies. Am J Clin Nutr. 2013;98(6 Suppl):1676S–81S.
Montague JA, Butler LM, Wu AH, et al. Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control. 2012;23(10):1635–41.
Ben-Shlomo Y, Evans S, Ibrahim F, et al. The risk of prostate cancer amongst black men in the United Kingdom: the PROCESS cohort study. Eur Urol. 2008;53(1):99–105.
Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci U S A. 2001;98(18):10350–5.
Suttie A, Nyska A, Haseman JK, Moser GJ, Hackett TR, Goldsworthy TL. A grading scheme for the assessment of proliferative lesions of the mouse prostate in the TRAMP model. Toxicol Pathol. 2003;31(1):31–8.
Gupta S, Ahmad N, Mohan RR, Husain MM, Mukhtar H.Prostate cancer chemoprevention by green tea: in vitro and in vivo inhibition of testosterone-mediated induction of ornithine decarboxylase. Cancer Res. 1999 May 1;59(9):2115–20.
Harper CE, Patel BB, Wang J, Eltoum IA, Lamartiniere CA. Epigallocatechin-3-gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: mechanisms of action. Prostate. 2007;67(14):1576–89.
Khan N, Adhami VM, Mukhtar H. Review: green tea polyphenols in chemoprevention of prostate cancer: preclinical and clinical studies. Nutr Cancer. 2009;61(6):836–41.
Kim S, Ku J-L. Metformin induces apoptotic cell death and inhibits CD133+ cancer stem cells in 5-Fu-resistance colorectal cancer cells. AACR Annual Meeting 2014; 4/6/14; San Diego, CA: AACR; 2014.
Siddiqui IA, Zaman N, Aziz MH, et al. Inhibition of CWR22Rnu1 tumor growth and PSA secretion in athymic nude mice by green and black teas. Carcinogenesis. 2006;27(4):833–9.
Nam S, Smith DM, Dou QP. Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo. J Biol Chem. 2001;276(16):13322–30.
Le Y, Cui Y, Iribarren P, Ying G, Wang JM. Manipulating chemoattractant and receptor genes. In Vivo. 2002;16(1):1–23.
Kazi A, Wang Z, Kumar N, Falsetti SC, Chan TH, Dou QP. Structure–activity relationships of synthetic analogs of (–)-epigallocatechin-3-gallate as proteasome inhibitors. Anticancer Res. 2004;24(2B):943–54.
Smith DM, Wang Z, Kazi A, Li LH, Chan TH, Dou QP. Synthetic analogs of green tea polyphenols as proteasome inhibitors. Mol Med. 2002;8(7):382–92.
Kazi A, Daniel KG, Smith DM, Kumar NB, Dou QP. Inhibition of the proteasome activity, a novel mechanism associated with the tumor cell apoptosis-inducing ability of genistein. Biochem Pharmacol. 2003;66(6):965–76.
Adhami VM, Ahmad N, Mukhtar H. Molecular targets for green tea in prostate cancer prevention. J Nutr. 2003;133(7 Suppl):2417S-24S.
Liang YC, Lin-shiau SY, Chen CF, Lin JK. Suppression of extracellular signals and cell proliferation through EGF receptor binding by (–)-epigallocatechin gallate in human A431 epidermoid carcinoma cells. J Cell Biochem. 1997;67(1):55–65.
Chung JY, Huang C, Meng X, Dong Z, Yang CS. Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure–activity relationship and mechanisms involved. Cancer Res. 1999;59:4610–7.
Liang YC, Lin-Shiau SY, Chen CF, Lin JK. Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (–)-epigallocatechin-3-gallate. J Cell Biochem. 1999;75(1):1–12.
Khan N, Mukhtar H. Modulation of signaling pathways in prostate cancer by green tea polyphenols. Biochem Pharmacol. 2013;85(5):667–72.
Gupta S, Hussain T, Mukhtar H. Molecular pathway for (–)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys. 2003;410:177–85.
Yang CS, Wang H. Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor? Clin Invest. 2013;123(2):556–58.
Rizzi F, Naponelli V, Silva A, et al. Polyphenon E®, a standardized green tea extract, induces endoplasmic reticulum stress, leading to death of immortalized PNT1a cells by anoikis and tumorigenic PC3 by necroptosis. Carcinogenesis. 2014;35(4):828–39.
Hagen RM, Chedea VS, Mintoff CP, Bowler E, Morse HR, Ladomery MR. Epigallocatechin-3-gallate promotes apoptosis and expression of the caspase 9a splice variant in PC3 prostate cancer cells. Int J Oncology. 2013.
Connors SK, Chornokur G, Kumar NB. New insights into the mechanisms of green tea catechins in the chemoprevention of prostate cancer. Nutr Cancer. 2012;64(1):4–22.
Saverio b, Pierpaola D, Serenella A, Cesare C, Bruno M, Auro T, Arnaldo C. Tumor progression in accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res. 2000;60:23–30.
Scaltriti M, Brausi M, Amorosi A, et al. Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer. Int J Cancer. 2004;108(1):23–30.
Bettuzzi S, Scorcioni F, Astancolle S, Davalli P, Scaltriti M, Corti A. Clusterin (SGP-2) transient overexpression decreases proliferation rate of SV40-immortalized human prostate epithelial cells by slowing down cell cycle progression. Oncogene. 2002;21(27):4328–34.
Grassilli E, Bettuzzi S, Monti D, Ingletti MC, Franceschi C, Corti A. Studies on the relationship between cell proliferation and cell death: opposite patterns of SGP-2 and ornithine decarboxylase mRNA accumulation in PHA-stimulated human lymphocytes. Biochem Biophys Res Commun. 1991;180(1):59–63.
July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002;50(3):179–88.
Pucci S, Bonanno E, Pichiorri F, Angeloni C, Spagnoli LG. Modulation of different clusterin isoforms in human colon tumorigenesis. Oncogene. 2004;23(13):2298–304.
Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 2001;480–481:243–68.
Garcia R, Bowman TL, Niu G, et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 2001;20(20):2499–513.
Segev DL, Hoshiya Y, Stephen AE, et al. Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary epithelial cells in vivo. J Biol Chem. 2001;276(29):26799–806.
Drexler HC. Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci U S A. 1997;94(3):855–60.
Jentsch S. Ubiquitin-dependent protein degradation: a cellular perspective. Trends Cell Biol. 1992;2(4):98–103.
Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol. 1995;7(2):215–23.
Dou QP, McGuire TF, Peng Y, An B. Proteasome inhibition leads to significant reduction of Bcr-Abl expression and subsequent induction of apoptosis in K562 human chronic myelogenous leukemia cells. J Pharmacol Exp Ther. 1999;289(2):781–90.
Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999;59(11):2615–22.
Voges D, Zwickl P, Baumeister W. The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem. 1999;68:1015–68.
Groll M, Heinemeyer W, Jager S, Ullrich T, Bochtler M, Wolf DH, Huber R. The catalytic sites of 20S proteasomes and their role in subunit maturation: a mutational and crystallographic study. Proc Natl Acad Sci U S A. 1999;96(20):10976–83.
Chen S, Fribley A, Wang CY. Potentiation of tumor necrosis factor-mediated apoptosis of oral squamous cell carcinoma cells by adenovirus-mediated gene transfer of NF-kappaB inhibitor. J Dent Res. 2002;81(2):98–102.
Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell. 2002;109 Suppl:S81–96.
An B, Goldfarb RH, Siman R, Dou QP. Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ. 1998;5(12):1062–75.
Li B, Dou QP. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc Natl Acad Sci U S A. 2000;97(8):3850–5.
Dimmeler S, Breitschopf K, Haendeler J, Zeiher AM. Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link between the apoptosome and the proteasome pathway. J Exp Med. 1999;189(11):1815–22.
Caporali A, Davalli P, Astancolle S, D’Arca D, Brausi M, Bettuzzi S, Corti A. The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression. Carcinogenesis. 2004;25(11):2217–24.
Leskov KS, Klokov DY, Li J, Kinsella TJ, Boothman DA. Synthesis and functional analyses of nuclear clusterin, a cell death protein. J Biol Chem. 2003;278(13):11590–600.
Chow HH, Cai Y, Alberts DS, et al. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev. 2001;10(1):53–8.
Chow HH, Hakim IA, Vining DR, et al. Effects of repeated green tea catechin administration on human cytochrome P450 activity. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2473–6.
Pisters KM, Newman RA, Coldman B, et al. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol. 2001;19(6):1830–8.
Chow HH, Cai Y, Hakim IA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res. 2003;9(9):3312–9.
Ullmann U, Haller J, Decourt JD, Girault J, Spitzer V, Weber P. Plasma-kinetic characteristics of purified and isolated green tea catechin epigallocatechin gallate (EGCG) after 10 days repeated dosing in healthy volunteers. Int J Vitam Nutr Res. 2004;74(4):269–78.
Ullmann U, Haller J, Decourt JP, et al. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res. 2003;31(2):88–101.
Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A. 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. 2006;66(2):1234–40.
Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol. 2008;54(2):472–3.
Jatoi A, Ellison N, Burch PA, et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer. 2003;97(6):1442–6.
McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA. 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). 2009;2(7):673–82.
Nguyen MM, Ahmann FR, Nagle RB, et al. Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. Cancer Prev Res (Phila). 2012;5(2):290–8.
Adhami VM, Siddiqui IA, Sarfaraz S, Khwaja SI, Hafeez BB, Ahmad N, Mukhtar H. Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin Cancer Res. 2009;15(6):1947–53.
Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst. 1996 Nov 6;88(21):1560–70.
Omenn GS. Chemoprevention of lung cancers: lessons from CARET, the beta-carotene and retinol efficacy trial, and prospects for the future. Eur J Cancer Prev. 2007;16(3):184–91.
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371–88.
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA.2006 Jun 21;295(23):2727–41. Epub 2006 Jun 5.
Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006 Aug 31;355(9):873–84.
Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000 Jun 29;342(26):1946–52.
Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003 Mar 6;348(10):891–9.
Zell JA, Pelot D, Chen WP, McLaren CE, Gerner EW, Meyskens FL. Risk of cardiovascular events in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas. Cancer Prev Res (Phila). 2009 Mar;2(3):209–12.