Mechanisms of Chemoprevention by Resveratrol

白藜芦醇的化学预防机制

• 批准号: 7154712
• 负责人: RAKESH K. SRIVASTAVA
• 金额: $ 19.73万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154712
• 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（由申请人提供）：在我们的努力中，我们建议您预防和治疗人类前列腺癌，我们建议研究一种饮食剂白藜芦醇，这是一种在葡萄和葡萄酒中发现的多酚化合物。白藜芦醇对与肿瘤起始，促进和进展相关的各种细胞事件的抑制作用产生了巨大的抑制作用，因此作为前列腺癌的化学预防剂的发育有很大的希望。此外，白藜芦醇使前列腺癌细胞趋向于追踪（与TNF相关的凋亡诱导配体），这是一种生物学上重要的细胞因子。除这些进步外，白藜芦醇抑制增殖并诱导肿瘤细胞中凋亡的细胞内机制尚未完全定义。评估白藜芦醇针对前列腺癌疗效的总体原理来自流行病学数据和我们的初步研究。我们假设白藜芦醇将在抑制人前列腺癌细胞的生长中非常有效，因为它（a）通过上调死亡受体和caspases的激活以及（b）激活转录因子的FOXO家族而诱导凋亡。该项目的具体目的是：（1）确定白藜芦醇抑制增殖并诱导人前列腺癌细胞凋亡的细胞内机制；并确定白藜芦醇使前列腺癌细胞落后的分子机制； （2）检验转录因子家族调节Bcl-2家族成员的机制，细胞周期调节基因和用白藜芦醇处理的前列腺癌细胞中的细胞凋亡； （3）确定白藜芦醇和TRAIL对裸鼠体内人类前列腺癌异种移植物的生长的影响，并确定白藜芦醇的机理和TRAIL介导的前列腺癌异种移植物的体内生长抑制。具体而言，研究旨在确定线粒体和/或死亡受体途径的贡献，以及在白藜芦醇诱导的凋亡中PI3-K/AKT/FOXO活性。将确定与FOXO转录因子的下游凋亡相关靶标。白藜芦醇和TRAIL的相互作用将根据异种移植生长和肿瘤回归进行评估。 因此，可以将基于白藜芦醇的策略用于预防和治疗前列腺癌，从长远来看，它可能对人类前列腺癌的整体发病率产生深远影响。