Mechanisms of Chemoprevention by Resveratrol

白藜芦醇的化学预防机制

基本信息

批准号：
7216268
负责人：
RAKESH K. SRIVASTAVA
金额：
$ 16.82万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
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/7216268
关键词：
Ablation Address Affect Androgens Antiandrogen Therapy Apoptosis Caspase Cell Cycle Cell Cycle Arrest Cell Death Induction Cell Proliferation Cells Cessation of life Chemoprevention Chemopreventive Agent Cultured Cells Data Development Disease regression Elderly Employee Strikes Event Family Family member Gene Targeting Goals Grapes Growth Hormones Incidence Induction of Apoptosis Knowledge Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Mitochondria Molecular Nude Mice Pathway interactions Patients Prevention Prevention strategy Prevention therapy Prostate Refractory Disease Regulator Genes Relapse Research Design Research Project Grants Resistance Resveratrol Role Standards of Weights and Measures Stream TNF-related apoptosis-inducing ligand Testing Therapeutic Tissues Up-Regulation Wine Work Xenograft procedure aging population base cancer cell cytokine efficacy evaluation in vivo male member neoplastic cell pre-clinical research receptor size transcription factor tumor tumor growth tumor initiation tumor xenograft

项目摘要

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）：在我们努力寻找用于预防和治疗人类前列腺癌的新的、毒性较小的疗法的过程中，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。白藜芦醇对与肿瘤发生、促进和进展相关的多种细胞事件具有显着的抑制作用，因此作为前列腺癌的化学预防剂具有广阔的发展前景。此外，白藜芦醇使前列腺癌细胞对 TRAIL（TNF 相关凋亡诱导配体）敏感，这是一种生物学上重要的细胞因子。除了这些进展之外，白藜芦醇抑制肿瘤细胞增殖并诱导肿瘤细胞凋亡的细胞内机制尚未完全明确。评估白藜芦醇抗前列腺癌功效的总体原理来自流行病学数据和我们的初步研究。我们假设白藜芦醇能够非常有效地抑制人类前列腺癌细胞的生长，因为它能够 (a) 通过上调死亡受体和 Bcl-2 家族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。该项目的具体目标是：（1）确定白藜芦醇抑制人前列腺癌细胞增殖并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) 探讨转录因子FOXO家族对白藜芦醇处理的前列腺癌细胞中Bcl-2家族成员、细胞周期调控基因及细胞凋亡的调节机制； (3)研究白藜芦醇和TRAIL对裸鼠体内人前列腺癌移植瘤生长的影响，探讨白藜芦醇和TRAIL介导的体内前列腺癌移植瘤生长抑制的机制。具体来说，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标将被确定。白藜芦醇和 TRAIL 的交互作用将根据异种移植物生长和肿瘤消退进行评估。因此，基于白藜芦醇的策略可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总体发病率产生深远的影响。