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Department of Dermatology, University of Wisconsin, Madison, WI 53706
3 To whom correspondence should be addressed. E-mail: hxm{at}medicine.wisc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • green tea • prostate cancer • chemoprevention • metalloproteinases • cell cycle • apoptosis
Prostate cancer (PCa)4 is a major public health concern and a leading cause of cancer-related deaths among males in the U.S. (
1,
2). According to estimates of the American Cancer Society, for the year 2002, 
189,000 new cases of PCa and 30,200 PCa-related deaths were predicted (
2). It is therefore necessary to intensify our efforts to better understand this disease and develop novel approaches for its prevention and treatment. Chemoprevention involving the use of natural or synthetic agents to suppress, block or reverse the process of carcinogenesis could be an effective approach to reduce the incidence of PCa (
3–
13). Indeed, PCa represents an excellent candidate disease for chemoprevention, because it is typically diagnosed in elderly men; even a modest delay in the neoplastic development achieved through pharmacological or therapeutic intervention could result in substantial reduction in the incidence of the clinically detectable disease. Consistent with this assumption, there is intense activity in defining chemopreventive agents and molecular targets for PCa chemoprevention (
14–
26). Among the many such agents that are available, for a variety of reasons, naturally occurring nontoxic dietary substances are preferred. Also, the major targets of marketing such products are PCa patients. Among these dietary products are many formulations of green tea that are specially marketed for PCa patients.
Green tea, derived from the plant Camellia sinensis, is a popular beverage in some parts of the world. Studies conducted on cell-culture systems and animal models as well as human epidemiological studies show that the polyphenols that are present in green tea could afford protection against a variety of cancer types ( 14– 26). Some studies also suggest that these polyphenols could be developed as therapeutic agents for some cancer types ( 27– 28). An important fact in favor of the use of green tea against PCa is that the incidence of this disease is very low in the Asian population, which in addition to consuming low-fat and high-fiber diets regularly consumes green tea ( 29). Although these studies are correlative and like most nutritional epidemiological observations are inconclusive, laboratory data suggest that the polyphenols present in green tea may possess a chemopreventive effect against PCa in humans. At least two epidemiological studies ( 30, 31) show that people who regularly consume tea have a lower incidence of PCa. Because of these encouraging facts, we initiated a program on chemoprevention of PCa by green tea and its major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG). We provide evidence for the PCa chemopreventive effects of green tea that is based on a variety of studies on cell-culture systems and animal models. This article highlights our in vitro and in vivo findings. Based on the available evidence, it appears that there are multiple targets by which green tea could afford PCa chemopreventive effects.
Cell-culture studies
A variety of cell-culture studies show multiple targets as a mechanism of action of green tea polyphenols (GTP) or EGCG. The major studies that show the targets of PCa chemoprevention by EGCG are discussed below and summarized in Table 1.
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Green tea and ornithine decarboxylase. Studies demonstrate that prostate contains some of the highest concentrations of polyamines and polyamine-metabolizing enzymes ( 39). We reasoned that ornithine decarboxylase (ODC), which is a rate-limiting enzyme of the polyamine pathway, could serve as the target for prevention and therapy of human PCa. In the prostate, ODC activity is regulated by androgens ( 40). When LNCaP cells are treated with testosterone, a significant increase in the level of ODC enzyme activity is observed ( 23). Pretreatment of LNCaP cells with GTP inhibits the testosterone-mediated increase in ODC activity and ODC mRNA, which suggests that ODC could be a target of green tea–mediated cell-growth inhibition. In the same study, the effects of testosterone and/or GTP on anchorage-independent growth of LNCaP cells by soft-agar colony-formation assay was ascertained. Researchers identified that testosterone induces a significant increase in the ability of the cells to form colonies, and this increase is inhibited by GTP in a dose-dependent fashion.
Green tea and proteasome activity.
The 20S proteasome, which is a multicatalytic complex (700 kDa), constitutes the catalytic key component of the ubiquitous proteolytic machinery 26S proteasome (
41–
46). There are three major proteasomal activities: chymotrypsin-like, trypsin-like and peptidyl-glutamyl peptide hydrolyzing activities (
41,
46). The ubiquitin-proteasome system plays a critical role in the specific degradation of cellular proteins (
47), and two of the proteasome functions are to allow tumor cell-cycle progression and to protect tumor cells against apoptosis (
48). The chymotrypsin-like but not the trypsin-like activity of the proteasome is associated with tumor-cell survival (
49,
50). Many cell-cycle and cell-death regulators are identified as targets of the ubiquitin-proteasome–mediated degradation pathway. Proteasome inhibitors are able to induce tumor-growth arrest, and tea consumption is correlated with cancer prevention. Nam et al. (
51) shows that an ester bond that contains tea polyphenols such as EGCG potently and specifically inhibits the chymotrypsin-like activity of the proteasome in vitro at concentrations that are found in the serum of green-tea drinkers. Atomic orbital energy analyses and high-performance liquid chromatography suggest that the carbon of the polyphenol ester bond is essential for targeting and thereby inhibiting the proteasome in cancer cells. This inhibition of the proteasome by EGCG in several tumor and transformed cell lines results in the accumulation of two proteasome substrates, p27/Kip1 and I
B-
, which is an inhibitor of transcription factor nuclear factor-B (NF-B), followed by growth arrest in the G1 phase of the cell cycle. Furthermore, compared with their simian virus–transformed counterparts, the parental normal human fibroblasts are much more resistant to EGCG-induced p27/Kip protein accumulation and G1 arrest (
51). This study suggests that proteasome is a cancer-related molecular target of tea polyphenols, and that inhibition of proteasome activity by ester bond–containing polyphenols may contribute to the cancer-preventive effects of tea.
Green tea and cDNA-array studies.
To further identify the molecular targets of PCa chemoprevention by EGCG, we employed a cDNA microarray technique (
52). We concentrated on a total of 250 genes associated with kinases and phosphatases that have biological functions associated with a variety of known signal transduction pathways such as cell cycle, apoptosis and metabolic biosynthesis. LNCaP cells were treated with or without 12 µmol EGCG/L for 12 h. EGCG-treated cDNA labeled with cyanine-3 and the control cDNA labeled with cyanine-5 were mixed and overlaid on the microarray, and the competitive binding for each gene was carried out. Analysis of the image from the cDNA microarray reveals a total of 25 genes (
Table 2) that show a significant response to EGCG. Of these, the expression of 16 genes is found to be significantly increased as a result of EGCG treatment, and 9 genes are found to be significantly repressed (
52) by EGCG. Intriguingly, all of these genes belong to different regulatory pathways, which suggests that EGCG affects multiple cellular events. The fact that 90% of the genes remain unaffected by EGCG indicates that these nonresponsive genes are not the transcriptional regulatory targets in the early stage of the EGCG-mediated effect. Also, EGCG was not found to affect genes such as cell-division cycle (cdc2) and cyclin-dependent kinase (Cdk) that regulate cell cycle, although EGCG is known to cause cell-cycle dysregulation, which suggests that posttranslational control of these proteins is more important than transcriptional regulation. Of the nine genes repressed by EGCG, six belong to the G-protein signaling network. Among these genes, the repression of protein kinase C (PKC)- is most prominent. The expression of the PKC- form is further validated by RNA slot blot hybridized with a PKC-–specific probe. EGCG decreases PKC- gene expression by approximately threefold. The repression of the PKC- gene is interesting, because PKC are involved in diverse cellular functions such as differentiation, growth control, tumor promotion and cell death (
53). PKC also are involved in the regulation of the cell cycle during G1 progression and G2/M transition (
54). Recent studies suggest that inhibition of PKC- gene expression could inhibit cell proliferation in the animal tumor model and in some human cancer-cell lines (
53).
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gene expression, which is a tumor-suppressor gene candidate that is frequently deleted in some human cancers (
55,
56), may have a role in PCa prevention mediated by EGCG. Prostatic acid phosphatase might help inhibit the growth rate by deactivation of erbB-2 and p38 mitogen-activated protein kinase (
57). Pyrroline-5-carboxylate, an endogenous proline-derived metabolite, is shown (
58) to inhibit cell proliferation and survival in some cancer cells, and an increase in the gene expression of pyrroline 5-carboxylate synthase by EGCG might display similar inhibitory effects in PCa cells. Five genes whose regulatory relationship with cell-growth control is not well understood to date are found to be induced by EGCG (see Table 2); these include tyrosine receptor kinase type E (Trk E), adenylate kinase 2A, protein tyrosine phosphatase, JAR/receptor-like protein tyrosine phosphatase and glomerular epithelial protein-l. The prototype of TrkE, Trk type A, is a protooncogene and functions as a transmembrane receptor to which endogenous nerve-growth factor binds and signals the onset of cell proliferation ( 59). TrkE gene expression was increased by approximately twofold in our slot blotting analysis. Because neurotrophin receptors can functionally inhibit one another's actions to mediate the effects of neurotrophins ( 59), we speculated that EGCG-induced TrkE gene expression may negatively modulate the proliferation signal in prostate cells. The functional diversity of these responsive gene candidates illustrates the complex nature of molecular interaction during the early stage of PCa prevention by EGCG. These genes may prove useful as therapeutic targets for PCa.
Animal studies
Studies on animal models show the usefulness of green tea polyphenols on PCa chemoprevention. These studies identify the targets for PCa chemoprevention by green tea under in vivo situations; the important work in this direction is discussed below and summarized in Table 3.
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Green tea and 5-reductase.
The enzyme steroid 5-reductase catalyzes the conversion of testosterone to 5-dihydrotestosterone. In humans, 5-reductase activity is critical for certain aspects of male sexual differentiation and may be involved in the development of benign prostatic hyperplasia, alopecia, hirsutism and PCa. Liao et al. (
62) showed that EGCG is a potent inhibitor of 5-reductase in cell-free assays but not in whole-cell assays, which suggests that it can regulate androgen action in target organs. A subsequent study by Hiipakka et al. (
63) showed that replacement of the gallate ester in EGCG with long-chain fatty acids produces potent 5-reductase inhibitors that are active in both cell-free and whole-cell assay systems.
Green tea and insulin-like growth factor and insulin-like growth factor binding protein-3. To have relevance to humans, we reasoned that PCa chemoprevention studies should be conducted on animal models that closely emulate human disease and possess surrogate endpoint biomarkers for rapid evaluation of chemopreventive and/or therapeutic agents. The transgenic adenocarcinoma of the mouse prostate (TRAMP) is one such model that mimics progressive forms of human disease and locations of cancer in natural tissue microenvironments without the need for any chemical or hormonal treatment ( 64). We conducted experiments in which TRAMP mice at 8 wk of age were given a 0.1% solution of GTP in tap water as the sole source of drinking fluid for 24 wk. An important observation of this work is that oral infusion of a human achievable dose of green tea (equivalent to 6 cups of green tea/d) results in significant inhibition in development and progression of PCa ( 26). In GTP-fed animals, no metastasis was detected, and most notably in these animals, increased tumor-free and overall survival rates were observed. High levels of circulating serum insulin-like growth factor (IGF-I) levels are associated with increased risk of several common cancers including PCa, and serum IGF-binding protein (IGFBP)-3 suppresses the mitogenic action of IGF-I ( 65). Because epidemiological studies implicate deregulation of the IGF axis in PCa progression ( 65), we measured the effect of GTP consumption by TRAMP mice on serum IGF-I and IGFBP-3 levels. GTP infusion to TRAMP mice causes significant inhibition of IGF-I and restoration of IGFBP-3 levels ( 26). These data suggest that the IGF-I and IGFBP-3 autocrine/paracrine loop is a target for PCa chemoprevention by green tea. Additionally, our studies demonstrate that feeding GTP to TRAMP mice results in increased apoptosis in the prostate ( 26). Based on these data, we suggest that GTP consumption by TRAMP mice causes significant apoptosis of PCa cells, which possibly results in reduced dissemination of cancer cells and thereby causes inhibition of PCa development. This observation validates our in vitro studies, which indicate that apoptosis is an endpoint target for chemoprevention of PCa by GTP.
Green tea and cDNA-array studies. Recently we investigated the expression of various genes with biological function that are associated with metastasis and angiogenesis in TRAMP. Using a gene-array technique (SuperArray, Bethesda, MD), a total of 96 genes were examined, each of which belongs to a metastasis- and/or angiogenesis-related pathway. Analysis of the metastasis-related gene array reveals a total of seven genes with expression that is more than fivefold higher and a total of five genes with expression that is more than fivefold lower ( Table 4) in the dorsolateral prostate of TRAMP mice as compared with nontransgenic littermates. When the angiogenesis-related genes are examined, fivefold higher expression is observed in 10 genes, but four genes are found to be repressed ( Table 5).
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EGCG is shown to inhibit tumor growth by inhibiting VEGF ( 73, 74). One of the hydrolases that is implicated in the degradation of extracellular matrix and tumor invasion, u-PA is shown to be inhibited by EGCG ( 75, 76). It is speculated that EGCG inhibits u-PA, which is upstream in the enzymatic cascade that ends with MMP-2 and MMP-9. However, because EGCG concentration is much lower in the plasma than that actually required to inhibit u-PA, it is likely that EGCG acts as a direct inhibitor of MMP-2 and MMP-9. It is known from studies with tumor cells that synthetic MMP inhibitors may induce cell-cycle arrest and even promote apoptosis. The MMP inhibitor batimastat (BB-94) is shown to enhance apoptosis and block ovarian cancer cells in the G0/G1 phase of the cell cycle. Another MMP inhibitor, AG3340, promotes apoptosis in human PCa and colon carcinoma models ( 77). The role of MMP and their inhibitors in the regulation of the cell cycle and apoptosis is still emerging.
Epidemiological studies
As yet, no detailed case-control study has been conducted to assess the effects of consumption of green tea for human PCa. All published data that seek an association between tea consumption and PCa risk have considered undefined tea preparations that are mostly black tea. At least two epidemiological studies show that people who regularly consume tea have a lower incidence of PCa ( 30, 31). In a prospective cohort study that employed 7,833 men of Japanese ancestry living in Hawaii, Heilbrun et al. ( 30) observe a weak but significant negative association between black-tea intake (>1 cup/d) and PCa incidence (P = 0.02). In a case-control study conducted in three geographical areas of Canada, Jain et al. ( 31) observe a decrease in PCa risk with tea intake of >2 cup/d. Other epidemiological studies conducted in Italy ( 78), Utah ( 79) and Canada ( 80) do not find any difference of risk for PCa between tea drinkers and nondrinkers. However, most of these studies include populations that are predominantly black-tea drinkers. It should be noted that most of these studies lack parallels for comparisons in the categorization of tea consumption, type of tea consumed and ethnicity of the subjects, which weakens the overall impact of the studies. Epidemiological investigations that seek an association between green tea intake and presence of PCa should be undertaken to establish the validity of cell culture and animal data to human PCa patients.
Clinical trials with green tea
One recent phase II clinical trial explored the antineoplastic effects of green tea in patients with metastatic androgen-independent PCa ( 81). In this study, 48 patients were instructed to take 6 g of green tea/d orally in 6 divided doses. Patients were monitored monthly for response and toxicity. The study concludes that green tea carries limited antineoplastic activity among patients with androgen-independent PCa. It should be noted, however, that this study was conducted on patients with metastatic androgen-independent PCa and therefore, in principle, does not assess the chemopreventive effects of green tea. For an ideal study, a population with high risk for PCa development should be considered.
Taken together, our studies and the data from other laboratories suggest that green tea and its constituents induce apoptosis, inhibit cell growth, arrest the progression of the cell cycle, inhibit angiogenesis and metastasis and importantly, inhibit prostate tumor growth in an animal model in which PCa progresses as in humans. Based on studies in cell-culture systems and cDNA-microarray analysis, it is apparent that there are multiple targets by which green tea and its constituent EGCG can afford PCa chemopreventive effects. We propose that there are at least three major molecular targets by which green tea could afford PCa chemopreventive effects. As depicted in Figure 1, the targets by which green tea affords PCa chemopreventive effects could work either independently or in concert with one another. It is noteworthy that green tea is one of the few agents known to inhibit tumorigenesis that is generally devoid of toxicity. PCa represents an excellent candidate disease for studying chemoprevention by dietary agents such as green tea, because it is typically diagnosed in elderly men; even a modest delay in the neoplastic development achieved through pharmacological or therapeutic intervention could result in a substantial reduction in the incidence of the clinically detectable disease. If our animal data could be validated in additional PCa models, then consideration could be given for developing green tea as a chemopreventive agent against PCa. However, because of very large gaps in our knowledge of the mechanisms of PCa prevention by green tea and discrepancies between epidemiological, laboratory and clinical studies, more extensive studies are needed to obtain conclusive evidence.
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FOOTNOTES |
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2 Original work cited in this paper was supported by U.S. Public Health Services grant R01-CA-78809 and American Institute for Cancer Research grant 00A030.
4 Abbreviations used: cdc2, cell-division cycle; Cdk, cyclin-dependent kinase; EGCG, (-)-epigallocatechin-3-gallate; GTP, green tea polyphenolic fraction; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; MMP, matrix metalloproteinase; ODC, ornithine decarboxylase; PCa, prostate cancer; PKC-, protein kinase C–; TRAMP, transgenic adenocarcinoma of the mouse prostate; Trk E, tyrosine receptor kinase type E; u-PA, urokinase-like plasminogen activator; VEGF, vascular endothelial growth factor.
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