Mechanisms of Chemoprevention by Resveratrol

白藜芦醇的化学预防机制

• 批准号: 7036480
• 负责人: RAKESH K. SRIVASTAVA
• 金额: $ 17.08万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036480
• 关键词: BCL2 gene /protein; antineoplastics; apoptosis; athymic mouse; carcinogenesis inhibitor; cell line; chemoprevention; cysteine endopeptidases; drug discovery /isolation; neoplasm /cancer remission /regression; plant extracts; prostate neoplasms; transcription factor; xenotransplantation

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.

描述(申请人提供)：在我们努力寻找预防和治疗人类前列腺癌的新的、毒性较低的疗法的过程中，我们建议研究一种膳食剂白藜芦醇，这是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、促进和发展相关的多种细胞事件具有显著的抑制作用，因此白藜芦醇作为前列腺癌的化学预防药物具有很大的发展前景。此外，白藜芦醇使前列腺癌细胞对TRAIL(肿瘤坏死因子相关的凋亡诱导配体)敏感，TRAIL是一种重要的生物学细胞因子。除了这些进展外，白藜芦醇抑制肿瘤细胞增殖和诱导肿瘤细胞凋亡的细胞内机制还不完全清楚。评估白藜芦醇治疗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。我们推测，白藜芦醇将高效地抑制人前列腺癌细胞的生长，因为它有能力(A)通过上调死亡受体和bc l-2家族的促凋亡成员以及激活caspase来诱导细胞凋亡，以及(B)激活FOXO转录因子家族。本项目的具体目的是：(1)确定白藜芦醇抑制人前列腺癌细胞增殖和诱导其凋亡的细胞内机制；以及白藜芦醇使前列腺癌细胞对TRAIL增敏的分子机制；(2)研究FOXO转录因子家族调控白藜芦醇治疗的前列腺癌Bcl2家族成员、细胞周期调控基因和细胞凋亡的机制；(3)确定白藜芦醇和TRAIL对人前列腺癌裸鼠移植瘤生长的影响，并确定白藜芦醇和TRAIL介导的体内抑制前列腺癌移植瘤生长的机制。具体地说，研究旨在确定线粒体和/或死亡受体通路以及PI3-K/Akt/FOXO活性在白藜芦醇诱导的细胞凋亡中的作用。FOXO转录因子下游的凋亡相关靶点将被确定。白藜芦醇和TRAIL的交互作用将从异种移植生长和肿瘤消退的角度进行评估。 因此，基于白藜芦醇的策略可以用于前列腺癌的预防和治疗，从长远来看，它可能会对人类前列腺癌的总体发病率产生深远的影响。