Resveratrol-Zinc Combination for Prostate Cancer

描述(由申请人提供)：前列腺癌(PCa)治疗需要新的基于机制的方法。许多研究表明锌在前列腺生物学中起着重要作用。锌在健康的前列腺中含量很高，而且 对前列腺功能很重要。有趣的是，在前列腺癌组织中，锌水平I显著降低，细胞内锌水平与前列腺癌的进展呈强烈的负相关。因此，锌似乎在前列腺癌的进展中起着关键作用。在肿瘤转化过程中，正常的前列腺上皮细胞是积累锌的柠檬酸产生细胞，似乎被代谢转化为失去积累锌的能力的柠檬酸氧化细胞。此外，研究表明锌转运蛋白(ZIPP)的表达减少，特别是ZIP1、ZIP2和ZIP3的表达可能与这种代谢转换有关。因此，很明显，PCa组织中zips的下调导致了锌的低生物积累。有趣的是，在PCa中，ZIP1的下调涉及RAS反应元件结合蛋白-1(RREB1)的过度表达。在前列腺癌细胞中恢复足够的锌水平已被证明可以抑制恶性潜能。此外，锌已被证明是一种预防前列腺癌的化学制剂，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，原位恶性前列腺细胞不能从循环中积累高水平的锌。因此，通过增加ZIP介导的锌转运来促进足够的锌在前列腺细胞中的生物积累的新方法可能对前列腺癌的治疗有用。白藜芦醇，一种在葡萄和红葡萄酒中发现的抗氧化剂，被证明能够对前列腺癌起到化学预防和治疗作用。最近的一项研究表明，白藜芦醇与锌联合应用显著增加了正常人前列腺上皮细胞中锌的浓度。我们的初步数据表明，1)白藜芦醇与锌联合应用能在前列腺癌细胞中产生更好的抗增殖反应，2)白藜芦醇-锌能增加前列腺癌细胞中ZIP蛋白(ZIP1、ZIP2和ZIP3)的水平。因此，根据已发表的研究和我们的初步数据，在这一应用中需要检验的假设是，白藜芦醇与锌联合使用时，将通过抑制RREB1介导的前列腺锌转运体(ZIP1、ZIP2和ZIP3)的增加来增强其生物积累，从而对前列腺癌产生显著优越的化学预防和治疗反应。提出了两个具体的目标：1)确定白藜芦醇和锌在体内是否对前列腺癌具有良好的化学预防和/或治疗作用；2)确定白藜芦醇和锌联合作用的机制(S)。我们的先导性研究结果可能会为白藜芦醇-锌联合治疗PCa的有效性提供有用的信息，使我们能够设计未来的深入研究，包括在人类群体中进行的PCa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.