Mechanisms of Chemoprevention by Resveratrol

白藜芦醇的化学预防机制

• 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
• 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

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）：在我们奋进识别用于预防和治疗人类前列腺癌的新的、毒性较小的疗法中，我们提议研究膳食剂白藜芦醇，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、发展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-相关凋亡诱导配体）敏感，TRAIL是一种生物学上重要的细胞因子。除了这些进展，白藜芦醇抑制肿瘤细胞增殖和诱导凋亡的细胞内机制尚未完全确定。白藜芦醇对前列腺癌的疗效评价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方面非常有效，这是由于其能够（a）通过上调Bcl-2家族的死亡受体和促凋亡成员以及激活半胱天冬酶来诱导凋亡，以及（B）激活转录因子的FOXO家族。本项目的具体目标是：（1）确定白藜芦醇抑制人前列腺癌细胞增殖和诱导凋亡的细胞内机制;确定白藜芦醇使前列腺癌细胞对TRAIL敏感的分子机制;（2）研究FOXO家族转录因子对Bcl-2家族成员的调控机制，研究白藜芦醇对前列腺癌细胞周期调控基因的影响及凋亡的影响;（3）研究白藜芦醇和TRAIL对人前列腺癌裸鼠移植瘤生长的影响，探讨白藜芦醇和TRAIL抑制前列腺癌裸鼠移植瘤生长的机制。具体而言，研究旨在确定线粒体和/或死亡受体途径以及PI 3-K/Akt/FOXO活性在白藜芦醇诱导的细胞凋亡中的作用。将鉴定FOXO转录因子的下游凋亡相关靶标。白藜芦醇和TRAIL的相互作用将在异种移植物生长和肿瘤消退方面进行评估。 因此，基于白藜芦醇的策略可以用于预防和治疗前列腺癌，并且从长远来看，它可能对人类前列腺癌的总体发病率产生深远的影响。