Mechanisms of Chemoprevention by Resveratrol

描述（由申请人提供）：在我们努力寻找新的，低毒的治疗方法来预防和治疗人类前列腺癌的过程中，我们建议研究一种膳食剂白藜芦醇，一种在葡萄和葡萄酒中发现的多酚化合物。白藜芦醇对与肿瘤发生、促进和进展相关的多种细胞事件具有显著的抑制作用，因此作为前列腺癌的化学预防剂具有很大的发展前景。此外，白藜芦醇使前列腺癌细胞对TRAIL （tnf相关的凋亡诱导配体）敏感，TRAIL是生物学上重要的细胞因子。除了这些进展外，白藜芦醇在肿瘤细胞中抑制增殖和诱导凋亡的细胞内机制尚未完全确定。评价白藜芦醇抗前列腺癌疗效的总体依据来自流行病学数据和我们的初步研究。我们假设白藜芦醇在抑制人类前列腺癌细胞生长方面非常有效，因为它能够(a)通过上调死亡受体和Bcl-2家族的促凋亡成员以及激活半胱天冬酶来诱导细胞凋亡，以及(b)激活FOXO转录因子家族。该项目的具体目的是：(1)确定白藜芦醇抑制人前列腺癌细胞增殖和诱导细胞凋亡的细胞内机制；并确定白藜芦醇使前列腺癌细胞对TRAIL敏感的分子机制；(2)探讨FOXO家族转录因子调控白藜芦醇治疗前列腺癌细胞中Bcl-2家族成员、细胞周期调控基因和细胞凋亡的机制；(3)测定白藜芦醇和TRAIL对裸鼠体内人前列腺癌异种移植物生长的影响，确定白藜芦醇和TRAIL介导的前列腺癌异种移植物体内生长抑制的机制。具体而言，研究旨在确定线粒体和/或死亡受体途径以及PI3-K/Akt/FOXO活性在白藜芦醇诱导的细胞凋亡中的作用。FOXO转录因子的下游凋亡相关靶点将被确定。白藜芦醇和TRAIL的相互作用将在异种移植物生长和肿瘤消退方面进行评估。

DESCRIPTION (provided by applicant): In our endeavor to identify new, less-toxic therapies for prevention and treatment of human prostate cancer, we propose to study a dietary agent resveratrol, a polyphenolic compound found in grapes and wine. Resveratrol exerts striking inhibitory effects on diverse cellular events associated with tumor initiation, promotion and progression, thus holds great promise for development as a chemopreventive agent for prostate cancer. Furthermore, resveratrol sensitizes prostate cancer cells to TRAIL (TNF-related apoptosis-inducing ligand), which is a biologically important cytokine. Besides these advances, the intracellular mechanisms by which resveratrol inhibits proliferation and induces apoptosis in tumor cells are not fully defined. Overall rationale for the evaluation of efficacy of resveratrol against prostate cancer comes from epidemiological data and from our preliminary studies. We hypothesize that resveratrol will be highly effective in suppressing growth of human prostate cancer cells, due to its ability to (a) induce apoptosis through upregulation of death receptors and proapoptotic members of the Bcl-2 family and activation of caspases, and (b) activate FOXO family of transcription factors. The specific aims of the project are: (1) To determine the intracellular mechanisms by which resveratrol inhibits proliferation and induces apoptosis in human prostate cancer cells; and to determine the molecular mechanisms by which resveratrol sensitizes prostate cancer cells to TRAIL; (2) To examine the mechanisms by which FOXO family of transcription factors regulate the Bcl-2 family members, cell cycle regulatory genes and apoptosis in prostate cancer cells treated with resveratrol; and (3) To determine the effect of resveratrol and TRAIL on growth of human prostate cancer xenografts in vivo in nude mice, and to determine the mechanism of resveratrol and TRAIL-mediated in vivo growth inhibition of prostate cancer xenografts. Specifically, studies are designed to determine the contribution of mitochondrial and/or death receptor pathways, and PI3-K/Akt/FOXO activity in resveratrol-induced apoptosis. The down-stream apoptosis-related targets of FOXO transcription factors will be identified. The interactive effects of the resveratrol and TRAIL will be assessed in terms of xenograft growth and tumor regression. Thus, resveratrol based strategies can be utilized for prevention and treatment of prostate cancer, and in the long-term it may have profound impact on the overall incidence of human prostate cancer.