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

• 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
• 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

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）：本区域申请中描述的研究是对前列腺癌进展审查小组（PRG）报告中的建议的响应。最近的数据表明，高硒（Se）摄入量或状态和植物雌激素（雌激素）的高摄入量各自提供了对前列腺癌的保护作用，并且它们的联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营养素在雄激素产生和前列腺生理学中的作用的研究，如......硒和植物雌激素“这项工作的目的是评估单独和联合高消费硒和硒酮对前列腺的癌症保护作用，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，在受孕时开始接触会产生有益的效果，而在性成熟后开始接触时则不会产生这种效果。为了确定这些作用的生化和分子机制，注意力将集中在由雄激素受体（AR）和NF-：B调节的过程。具体目标1是证明高膳食摄入的硒和维生素E酮，单独和组合，将抑制TRAMP（小鼠前列腺的转基因腺癌）小鼠前列腺癌的进展，这取决于饮食干预的时间。在不同的时间点（受孕、6、12和18周）开始并持续到不同的终点（6、12、18和24周），在2 × 2析因设计中，向TRAMP小鼠喂食足够或高Se以及低或高胆固醇的饮食。将测定每个时间点处死的所有动物的体重、泌尿生殖（GU）道重量、至可触及肿瘤的时间、病理学肿瘤分级和转移发生率。具体目标2是证明高膳食摄入的硒和孕酮，单独和组合，将减少雄激素受体（AR）和NF-：B的激活，并减少AR和NF-：B调节基因在TRAMP小鼠前列腺中的表达，这取决于膳食干预的时间。将通过ELISA测量雄激素、IGF-1和GH的血液水平，通过荧光测定法测量总硒，通过HPLC测量睾酮水平。将测定硒依赖性谷胱甘肽过氧化物酶和5 α-还原酶活性。AR和NF-：B活化将通过EMSA测定。将通过RT-PCR检测前列腺癌中AR-和NF-：B调节的相关基因的表达，其表达也被Se和/或孕酮修饰。这些试验将显示每种饮食成分的单独影响，每种成分对另一种代谢的调节作用，以及联合使用对目标终点的影响。这些测量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。这项工作将确定化学预防的机制，通过联合消费不同的保护性饮食成分和最佳时间在肿瘤发生的饮食干预。 公共卫生相关性：这项工作将完成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。这些包括1）“定义特定饮食因素在病因学和预防中的作用......癌症”; 2）增加“了解的作用…营养素的前列腺生理学”; 3）“这些营养素改变风险的机制”的定义;以及4）“营养素对前列腺中分子事件的影响”的证明。根据NIH的报告，“食物成分对前列腺分子事件的影响尚不清楚”。硒和维生素B1调节基因的发现将“确定关键饮食成分消费的生物标志物”。