MECHANISM OF SELENIUM POTENTIATION OF FINASTERIDE EFFICACY

硒增强非那雄胺功效的机制

• 批准号: 7254393
• 负责人: CLEMENT C IP
• 金额: $ 32.51万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254393
• 关键词: Address; Androgen Receptor; Androgen Suppression; Androgens; Apoptosis; Apoptotic; Binding; Cancer Control; Caspase; Chemoprevention; Chemosensitization; Complex; Depressed mood; Development; End Point; Enzymes; FOXO1A gene; Finasteride; Genes; Incidence; Intervention Studies; Laboratories; Malignant neoplasm of prostate; Mediating; Molecular; Numbers; Oxidoreductase; Phase; Phase III Clinical Trials; Placebo Control; Play; Prostate; Prostate Cancer Prevention Trial; Randomized; Receptor Signaling; Reporting; Research; Research Design; Risk; Role; Selenium; Signal Pathway; Signal Transduction; Stanolone; Supplementation; Testing; Testosterone; Xenograft Model; base; cancer risk; inhibitor/antagonist; prostate cancer prevention; restoration; transcription factor

Chemoprevention is an attractive approach to prostate cancer control. Several agents have been identified to be effective in reducing risk; among these are finasteride and selenium. In two independent phase III studies, treatment with finasteride or selenium decreased prostate cancer by 25% or 50%, respectively, although in the selenium trial, prostate cancer was not the primary endpoint. Finasteride is a competitive inhibitor of 5a-reductase, an enzyme responsible for the irreversible conversion of testosterone to dihydrotestosterone (DHT). Preliminary results from our laboratory showed that selenium depresses androgen receptor (AR)abundance, AR trans-activating activity and the expression of AR-regulated genes. Based on the above information, we propose to test the following hypotheses. Hypothesis #1: Since finasteride and selenium target different steps along the androgen signaling pathway, combining these two agents is likely to produce a cooperative or synergistic effect in prostate cancer prevention. Hypothesis #2: Disrupting the interaction between the DHT-AR complex with FOXO1A is critical for the anticancer effect of finasteride/selenium. FOXO1A is physically bound to and negatively regulated by DHT-AR. Through the mechanism of decreasing DHT by finasteride and AR availability by selenium, FOXO1A is expected to be liberated. As a transcription factor, FOXO1A induces the expression of a number of pro-apoptotic genes. The research plan consists of four specific aims. Aim 1: To determine (a) whether the combination of finasteride/selenium results in a further suppression of androgen signaling when compared to the single agent, and (b) whether finasteride has other effects on AR signaling beyond its known function of blocking 5a-reductase. Aim 2: To investigate the role of FOXO1A, a transcription factor negatively regulated by AR, in mediating the anticancer effect of finasteride and selenium. Aim 3: To study (a) the activation of initiator caspases and executioner caspases by finasteride or selenium, or both; and (b) whether restoration of AR signaling reverses the effect of each agent on caspase activation and caspase-mediated apoptosis. Aim 4: To validate the anticancer efficacy of finasteride/selenium and the accompanying molecular changes (information obtained from Aims 1to 3) in human prostate cancer xenograft models.

化学预防是前列腺癌控制的一种有吸引力的方法。几个探员 已确定可有效降低风险;其中包括氟氯噻嗪和硒。在两个独立 III期研究中，用非那肽或硒治疗可使前列腺癌减少25%或50%， 尽管在硒试验中，前列腺癌不是主要终点。Finaldade是一个 5a-还原酶的竞争性抑制剂，5a-还原酶是一种负责睾酮不可逆转化的酶 二氢睾酮（DHT）。我们实验室的初步结果表明，硒抑制 雄激素受体（AR）丰度、AR反式激活活性和AR调节基因的表达。 基于上述信息，我们提出测试以下假设。假设#1：由于 非那雄胺和硒作用于雄激素信号通路沿着不同步骤， 药物可能在前列腺癌预防中产生协同或协同作用。假设#2： 破坏DHT-AR复合物与FOXO 1A之间的相互作用对于DHT-AR的抗癌作用至关重要。 硒/硒。FOXO 1A与DHT-AR物理结合并受其负调控。通过 预计FOXO 1A是非那雄胺降低DHT和硒降低AR利用率的机制 解放了FOXO 1A作为一种转录因子，诱导许多促凋亡基因的表达。 研究计划包括四个具体目标。目标1：确定（a） 当与单用氟哌啶醇/硒相比时， （B）除其已知的阻断AR信号传导的功能外， 5 α-还原酶。目的2：研究AR负调控转录因子FOXO 1A在人乳腺癌中的作用， 介导非那肽和硒的抗癌作用。目的3：研究（a）引发剂的活化 半胱天冬酶和执行者半胱天冬酶;和（B）是否恢复AR 信号传导逆转每种试剂对胱天蛋白酶活化和胱天蛋白酶介导的细胞凋亡的作用。目标4： 验证非那肽/硒的抗癌疗效和伴随的分子变化 （从目的1至3获得的信息）。