Prevention of Prostate Cancer by Sulforaphane

萝卜硫素预防前列腺癌

• 批准号: 6954931
• 负责人: Shivendra Singh
• 金额: $ 29.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954931
• 关键词: BCL2 gene /protein; apoptosis; athymic mouse; cancer prevention; cysteine endopeptidases; densitometry; enzyme induction /repression; free radical oxygen; genetically modified animals; growth inhibitors; human tissue; immunocytochemistry; immunoprecipitation; isothiocyanates; neoplastic cell; plant extracts; prostate neoplasms; small interfering RNA; sulfur compounds; western blottings

DESCRIPTION (provided by applicant): This pre-clinical research project is based on the premise that sulforaphane (SFN; CH3-SO-(CH2)4-N=C=S), a constituent of many cruciferous vegetables including broccoli, may be used to inhibit onset and/or progression of human prostate cancer. Rationale for pre-clinical evaluation of SFN against prostate cancer derives from epidemiological data as well as the results of our preliminary studies, which led us to hypothesize that SFN will effectively suppress growth of prostate cancer due to its ability to trigger caspase-mediated apoptosis involving generation of reactive oxygen species (ROS) and Bcl-2 family proteins. We propose to test this hypothesis by: (1) Determining whether SFN-induced apoptosis is mediated by mitochondria-derived and/or non-mitochondrial ROS generation using PC-3 and LNCaP human prostate cancer cells as a model, (2) Determining the role of Bcl-2, Bax and Bak proteins in SFN-induced apoptosis using PC-3 and LNCaP cells, (3) Determining the relative contribution of intrinsic (mitochondria mediated activation of caspase-9) and extrinsic (death-receptor mediated activation of caspase-8) caspase pathways in apoptosis induction by SFN using PC-3 and LNCaP cells, (4) Determining the effect of oral administration of SFN on growth and regression of PC-3 and LNCaP xenografts in nude mice, and (5) Determining in vivo efficacy of SFN administration on prostate carcinogenesis using a transgenic mouse model (TRAMP). In specific aims 4 and 5, the tumor tissues from control and SFN treated mice will be analyzed for apoptosis index and levels of cell cycle and apoptosis regulating proteins to determine the extent to which SFN-induced molecular changes observed in cells (aims 1-3) correlate with its effect in vivo. In summary, the studies proposed in this application will (a) define the mechanism by which SFN inhibits growth of human prostate cancer cells, which may lead to identification of mechanism-based biomarkers potentially useful in future clinical trials, and (b) determine in vivo efficacy of SFN against prostate cancer using two different animal models, which is a prerequisite for initiation of clinical trials to determine its activity against human prostate cancer.

描述（由申请人提供）：该临床前研究项目基于以下前提：Sulforaphane（SFN; CH3-SO-（CH2）4-N = C = S）是许多包括西兰花（包括西兰花）的组成部分，可用于抑制人类前列腺癌的发作和/或进展。针对前列腺癌的SFN进行临时评估的基本原理源自流行病学数据以及我们的初步研究的结果，这使我们假设SFN将有效抑制前列腺癌的生长，因为它能够触发caspase介导的凋亡涉及反应性牛的产生的caspase介导的细胞增多（Ros）和Bcl-2家族蛋白蛋白（ROS）和BCL-2-2-2。我们建议通过：（1）确定SFN诱导的凋亡是否是通过使用PC-3和LNCAP人前列腺癌细胞作为模型来介导的，是通过线粒体衍生的和/或非细胞软骨ROS介导的，（2）使用BCL-2和BAK蛋白在SFN-诱导的APOPINCAP中的作用（2）固有（线粒体介导的caspase-9的激活）和外部（死亡受体介导的caspase-8）caspase途径在SFN诱导pC-3和LNCAP细胞中的caspase途径的相对贡献，（4）确定SFN对PC-3和LNC-3和LNC的生长效应（4）使用转基因小鼠模型（Tramp），SFN给药对前列腺癌发生的体内功效。在特定目标4和5中，将分析来自对照和SFN处理的小鼠的肿瘤组织的凋亡指数以及细胞周期的水平以及调节蛋白质的细胞周期水平，以确定SFN诱导的分子变化的程度（AIMS 1-3）与其在体内的作用相关（AIMS 1-3）。总而言之，该应用中提出的研究将（a）定义SFN抑制人类前列腺癌细胞生长的机制，这可能导致鉴定基于机制的生物标志物在将来的临床试验中可能有用，（（b）确定SFN对使用两种不同动物模型的SFN对临床癌症进行临时性癌症的活动，从而确定SFN对前列腺癌的疗效，以确定临床癌症的临床范围。