As prostate cancer (PCa) is a leading cause of cancer-related deaths among males in the US, it is necessary to develop novel treatments and chemopreventive approaches for this disease. PCa is an ideal disease for chemoprevention because it is typically diagnosed in men over 50 years of age and, therefore, even a modest delay achieved through intervention via chemoprevention could result in substantial reduction in the incidence of disease. Studies from the laboratory of the PI and others have shown remarkable cancer chemopreventive effects of green tea in animal tumor models and in epidemiological studies. Also, because the incidence of PCa is lower in some Japanese and Chinese populations consuming green tea on a regular basis, we hypothesized that green tea, specifically its constituent (-)-epigallocatechin- 3-gallate (EGCG), is effective for chemoprevention of PCa. To investigate this hypothesis we initiated a program on chemoprevention of PCa by green tea. In a recent study (PNAS 98:10350-5, 2001), employing a transgenic adenocarcinoma of the mouse prostate (TRAMP) that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea, at a human achievable dose (equivalent to six cups of green tea per day), significantly inhibits PCa development and its metastasis. One extremely significant observation was that oral infusion of green tea polyphenols resulted in an increased cancer free and overall survival of TRAMP mice. We extended these studies and found that in TRAMP there is an enhanced expression of genes related to metastasis (matrix metalloproteases, MMP-2 and MMP-9) and angiogenesis (vascular endothelial growth factor, VEGF). Using archival samples of Pca from our PNAS study, we found that oral feeding of green tea polyphenols as the sole source of drinking fluid to TRAMP mice resulted in significant inhibition of VEGF, MMP-2 and MMP-9 in dorsolateral prostate. This observation assumes significance and suggests the involvement of inhibition of angiogenesis and matrix degradation during green tea-mediated PCa chemoprevention. Of relevance to PCa, is the fact that once activated via certain stimuli, MMPs degrade insulin-like growth factor binding protein (IGFBP) resulting in the release of insulin-like growth factor (IGF). The central hypothesis to be tested in this proposal, based on our recent novel findings, is that """"""""EGCG imparts chemopreventive and possibly cancer therapeutic effects against PCa and its metastasis via MMP inhibition-mediated modulation in IGF/IGFBP-3 autocrine/paracrine loop"""""""".
The specific aims will investigate i) the chemopreventive potential of EGCG against the known markers of angiogenesls and metastasis in human prostate carcinoma cells and, ii) the chemopreventive potential of EGCG against PCa metastasis and angiogenesis in athymic nude mice implanted with PCa cells, and in TRAMP model. This study will help to identify novel pathways that may be modulated by EGCG in green tea that could be further exploited for prevention and/or treatment of prostate cancer. It is conceivable that with EGCG as lead compound, agents with superior efficacy could be developed.
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