Timing of Exposure to Selenium and Isoflavones and Prostate Cancer Prevention

接触硒和异黄酮的时机与预防前列腺癌

基本信息

批准号：
7882235
负责人：
MERRILL CHRISTENSEN
金额：
$ 22.5万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7882235
关键词：
Adenocarcinoma Androgen Receptor Androgens Animals Attention Biochemical Biological Assay Biological Markers Blood Body Weight Chemoprevention Chemopreventive Agent Conceptions Consumption Data Diet Dietary Component Dietary Factors Dietary Intervention Dietary intake Disease Progression EMSA Etiology Event Exposure to Five-Year Plans Fluorometry Food Gene Expression Genes Genitourinary system Goals High Pressure Liquid Chromatography Incidence Individual Insulin-Like Growth Factor I Intake Isoflavones Laboratories Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Mediating Metabolism Molecular Mus Neoplasm Metastasis Nutrient Oxidoreductase Palpable Pathway interactions Physiology Phytochemical Phytoestrogens Prevention Process Production Progress Review Group Prostate Prostate Cancer Progress Review Group Recommendation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Selenium Sexual Maturation Supplementation Time Tissues Transgenic Organisms United States National Institutes of Health Weight Work base cancer prevention design feeding glutathione peroxidase interest prostate cancer prevention protective effect public health relevance research study single molecule tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The research described in this AREA application is responsive to recommendations in the Report of the Prostate Cancer Progress Review Group (PRG). Recent data demonstrate that high selenium (Se) intake or status and high intake of phytoestrogens (isoflavones) each provide a protective effect against prostate cancer, and that their combined use may provide greater benefit than either dietary component alone. The PRG report recommends "Support studies aimed at better understanding of the roles in androgen production and in prostate physiology of nutrients such as ... selenium [and] phytoestrogens..." The objective of this work is to assess the cancer protective effects in prostate of high consumption of Se and isoflavones, individually and in combination, and to assess the critical effect of the timing of dietary exposure. Recent results from animal studies suggest that exposure begun at conception produces beneficial effects not seen when exposure is started after sexual maturation. To identify biochemical and molecular mechanisms for those effects, attention will focus on processes regulated by the androgen receptor (AR) and by NF-:B. Specific Aim 1 is to demonstrate that high dietary intake of Se and isoflavones, individually and in combination, will inhibit progression of prostate cancer in TRAMP (TRansgenic Adenocarcinoma of Mouse Prostate) mice, dependent on the timing of dietary intervention. Beginning at different time points (conception, 6, 12, and 18 weeks) and continuing to different end points (6, 12, 18 and 24 weeks), TRAMP mice will be fed diets adequate or high in Se, and low or high in isoflavones in a 2 X 2 factorial design. Measurement of body weight, genitourinary (GU) tract weight, time to palpable tumor, pathological tumor grade, and incidence of metastases will be determined for all animals sacrificed at each time point. Specific Aim 2 is to demonstrate that high dietary intake of Se and isoflavones, individually and in combination, will reduce activation of the androgen receptor (AR) and NF-:B, and decrease expression of AR- and NF-:B-regulated genes in prostates of TRAMP mice, dependent on the timing of dietary intervention. Blood levels of androgen, IGF-1, and GH will be measured by ELISAs, total Se by fluorometry, and isoflavone levels by HPLC. Se-dependent glutathione peroxidase and 5alpha-reductase activities will be assayed. AR and NF-:B activation will be determined by EMSA. Expression of AR- and NF-:B-regulated genes relevant in prostate cancer, whose expression is also modified by Se and/or isoflavones, will be examined by RT-PCR. These assays will show individual effects for each dietary component, the modifying effects each has on the other's metabolism, and the effects of combined use on the end points of interest. Correlation of these measures with time of dietary intervention and disease progression will identify the period(s) during tumor growth when supplementation may be most efficacious. This work will identify mechanisms of chemoprevention by combined consumption of different protective dietary components and the optimum time during tumorigenesis for dietary intervention. PUBLIC HEALTH RELEVANCE: This work will accomplish several objectives outlined by the Prostate Cancer Progress Review Group and by the NIH Five Year Plan "Planning for Prostate Cancer". These include 1) "defining the role of specific dietary factors in the etiology and prevention of...cancer"; 2) increasing "understanding of the roles in...prostate physiology of nutrients"; 3) definition of "the mechanisms by which these nutrients alter risk"; and 4) demonstration of "the effects of nutrients on molecular events in the prostate". According to the NIH report "the effect of food constituents on molecular events in the prostate is unknown". Discovery of Se- and isoflavone-regulated genes will "identify biomarkers of the consumption of key dietary components".

描述（由申请人提供）：本 AREA 申请中描述的研究是对前列腺癌进展审查小组 (PRG) 报告中的建议的回应。最近的数据表明，高硒 (Se) 摄入量或状态以及高植物雌激素（异黄酮）摄入量均具有预防前列腺癌的保护作用，并且它们的组合使用可能比单独使用任何一种饮食成分提供更大的益处。 PRG 报告建议“支持旨在更好地了解硒[和]植物雌激素等营养物质在雄激素产生和前列腺生理学中的作用的研究。”这项工作的目的是评估癌症保护作用前列腺单独或组合摄入大量硒和异黄酮，并评估饮食暴露时间的关键影响。最近的动物研究结果表明，在受孕时开始暴露会产生有益效果，而在性成熟后开始暴露则不会出现这种效果。为了确定这些效应的生化和分子机制，注意力将集中在雄激素受体 (AR) 和 NF-:B 调节的过程上。具体目标 1 是证明，单独或组合摄入高硒和异黄酮饮食将抑制 TRAMP（小鼠前列腺转基因腺癌）小鼠前列腺癌的进展，具体取决于饮食干预的时间。从不同的时间点（受孕、6、12 和 18 周）开始，持续到不同的终点（6、12、18 和 24 周），TRAMP 小鼠将被喂食充足或高硒、低或高硒的饮食。 2 X 2 析因设计中的异黄酮。将测定在每个时间点处死的所有动物的体重、泌尿生殖(GU)道重量、可触及肿瘤的时间、病理肿瘤分级和转移发生率的测量。具体目标 2 是证明，单独或组合摄入高硒和异黄酮饮食将减少雄激素受体 (AR) 和 NF-:B 的激活，并减少 AR- 和 NF-:B 调节基因的表达TRAMP 小鼠的前列腺中，依赖于饮食干预的时间。雄激素、IGF-1 和 GH 的血液水平将通过 ELISA 测量，总硒通过荧光测定法测量，异黄酮水平通过 HPLC 测量。将测定 Se 依赖性谷胱甘肽过氧化物酶和 5α 还原酶活性。 AR 和 NF-:B 激活将由 EMSA 确定。将通过 RT-PCR 检查与前列腺癌相关的 AR- 和 NF-:B 调节基因的表达，其表达也被 Se 和/或异黄酮修饰。这些测定将显示每种饮食成分的单独作用、每种成分对另一种代谢的改变作用，以及联合使用对目标终点的影响。这些措施与饮食干预时间和疾病进展的相关性将确定肿瘤生长期间补充可能最有效的时期。这项工作将通过联合食用不同的保护性饮食成分和肿瘤发生期间饮食干预的最佳时间来确定化学预防机制。公共健康相关性：这项工作将实现前列腺癌进展审查小组和 NIH 五年计划“前列腺癌规划”概述的几个目标。其中包括1）“定义特定饮食因素在……癌症的病因学和预防中的作用”； 2) 增加“对营养素在……前列腺生理学中的作用的理解”； 3）“这些营养素改变风险的机制”的定义； 4) 演示“营养物质对前列腺分子事件的影响”。根据美国国立卫生研究院的报告，“食物成分对前列腺分子事件的影响尚不清楚”。硒和异黄酮调节基因的发现将“识别关键膳食成分消耗的生物标志物”。