Novel mechanism-based approaches are needed for prostate cancer (PCa) management. A number of studies have suggested an important role of Zinc (Zn) in prostate biology. Zn exists in very high concentrations in the healthy prostate and is important for prostatic functions. Interestingly, in the cancerous prostatic tissue, the Zn level i significantly diminished and intracellular Zn levels have a strong inverse correlation with PCa progression. Therefore, Zn seems to play a critical role in PCa progression. During neoplastic transformation the normal prostate epithelial cells that are Zn-accumulating citrate producing cells seem to be metabolically transformed to citrate-oxidizing cells that lose the ability to accumulate Zn. Further, studies have suggested that a diminished expression of Zn transporter proteins (ZIPs), especially ZIP1, ZIP2 and ZIP3 may be associated with this metabolic transformation. Thus, apparently, down regulation of ZIPs in PCa tissue leads to low bioaccumulation of Zn. Interestingly, ZIP1 down-regulation in PCa was found to involve the overexpression of Ras responsive element binding protein-1 (RREB1). Restoration of adequate Zn levels in PCa cells has been shown to inhibit malignant potential. Further, Zn has been shown as a chemopreventive agent against PCa and supplementation with high dose of Zn may be useful. However, high dose of Zn is associated with many adverse effects. Further, malignant prostate cells in situ are incapable of accumulating high Zn levels from circulation. Therefore, novel means to enhance the bioaccumulation of sufficient Zn in the prostate cells via increasing ZIP-mediated Zn transport could be useful towards PCa management. Resveratrol, an antioxidant found in grapes and red wines, is shown to be capable of affording chemopreventive as well as therapeutic effects against PCa. A recent study has shown that resveratrol in combination with Zn dramatically increases the cellular Zn concentration in normal human prostate epithelial cells. Our preliminary data suggests that 1) a combination of resveratrol with Zn imparts a better anti-proliferative response in PCa cells, and 2) resveratrol-Zn increases ZIP proteins (ZIP1, ZIP2 and ZIP3) levels in PCa cells. Thus, based on published studies and our preliminary data, the hypothesis to be tested in this application is that resveratrol when combined with zinc will enhance its bioaccumulation, via RREB1 inhibition mediated increase in zinc-transporters (ZIP1, ZIP2 and ZIP3) in prostate, to impart a significantly superior chemopreventive and therapeutic response against PCa.
Two specific aims are proposed: 1) To determine if a combination of resveratrol and Zn imparts superior chemopreventive and/or therapeutic response against PCa in vivo;2) To determine the mechanism(s) of resveratrol-Zn combinatorial action. Outcome of our pilot study may provide useful information regarding the effectiveness of resveratrol-Zn combinatorial approach in PCa management, enabling us to design future in-depth studies including PCa clinical trial in human population.
In this application, we have proposed to study the usefulness of a resveratrol and Zn combinatorial approach for prevention as well as therapeutics of PCa. If successful, our study is likely to provide useful information regarding the effectiveness of a novel combinatorial approach in PCa management, enabling us to design future in-depth studies including PCa clinical trial in human population. This may ultimately have a significant impact on the health and well-being of males in the United States and other part of the world.
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