Resveratrol-Zinc Combination for Prostate Cancer

描述（由申请人提供）：前列腺癌（PCa）管理需要新的基于机制的方法。许多研究表明，锌（Zn）在前列腺生物学中起着重要作用。锌在健康前列腺中以非常高的浓度存在， 对前列腺功能很重要。有趣的是，在癌性前列腺组织中，Zn水平显著降低，并且细胞内Zn水平与PCa进展具有强的负相关性。因此，Zn似乎在PCa进展中起关键作用。在肿瘤转化过程中，正常的前列腺上皮细胞，即锌积累柠檬酸盐生产细胞，似乎代谢转化为柠檬酸盐氧化细胞，失去了积累锌的能力。此外，研究表明，锌转运蛋白（ZIPs），特别是ZIP 1，ZIP 2和ZIP 3的表达减少可能与这种代谢转化有关。因此，显然，PCa组织中ZIPs的下调导致Zn的低生物累积。有趣的是，发现PCa中ZIP 1的下调涉及Ras反应元件结合蛋白-1（RREB 1）的过表达。已显示PCa细胞中足够的Zn水平的恢复抑制恶性潜能。此外，锌已被证明是针对PCa的化学预防剂，并且补充高剂量的锌可能是有用的。然而，高剂量的锌与许多不良反应有关。此外，原位的恶性前列腺细胞不能从循环中积累高水平的Zn。因此，通过增加ZIP介导的Zn转运来增强足够的Zn在前列腺细胞中的生物累积的新方法可能对PCa管理有用。白藜芦醇是一种在葡萄和红葡萄酒中发现的抗氧化剂，被证明能够提供对PCa的化学预防和治疗作用。最近的一项研究表明，白藜芦醇与锌的组合显着增加正常人前列腺上皮细胞中的细胞锌浓度。我们的初步数据表明，1）白藜芦醇与锌的组合赋予PCa细胞更好的抗增殖反应，2）白藜芦醇-锌增加PCa细胞中的ZIP蛋白（ZIP 1，ZIP 2和ZIP 3）水平。因此，基于已发表的研究和我们的初步数据，在本申请中待检验的假设是白藜芦醇当与锌组合时将通过RREB 1抑制介导的前列腺中锌转运蛋白（ZIP 1、ZIP 2和ZIP 3）的增加来增强其生物累积，从而赋予针对PCa的显著上级化学预防和治疗应答。提出了两个具体目的：1）确定白藜芦醇和Zn的组合是否在体内赋予针对PCa的上级化学预防和/或治疗反应; 2）确定白藜芦醇-Zn组合作用的机制。我们的初步研究的结果可能提供有用的信息，白藜芦醇锌组合方法在PCa管理的有效性，使我们能够设计未来的深入研究，包括PCa在人群中的临床试验。

DESCRIPTION (provided by applicant): 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.