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.

化学预防是预防癌症控制的一种有吸引力的方法。有几个特工 被确定可有效降低风险；其中包括非那雄胺和硒。在两个独立中 第三阶段研究，对非那雄胺或硒的治疗使前列腺癌降低了25％或50％， 尽管在硒试验中，前列腺癌不是主要终点。非那雄胺是一个 5A-还原酶的竞争性抑制剂，这是一种负责睾丸激素不可逆转化的酶 到二氢睾丸激素（DHT）。我们实验室的初步结果表明硒降低 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，我们建议检验以下假设。假设1：自 Finastalide和Selenium沿雄激素信号通路的不同步骤，结合了这两个步骤 代理可能会在预防前列腺癌中产生合作或协同作用。假设2： 破坏DHT-AR复合物与FoxO1a之间的相互作用对于抗癌作用至关重要 非那雄胺/硒。 FoxO1a在身体上与DHT-AR的身体约束并负面调节。通过 硒降低DHT和AR可用性减少DHT的机制，预计FOXO1A将为 解放。作为转录因子，FOXO1A诱导许多促凋亡基因的表达。 研究计划由四个具体目标组成。目标1：确定（a）是否组合 与单个 代理和（b）非那雄胺是否对AR信号的其他影响超出其已知的阻塞功能 5A还原酶。目的2：研究FOXO1A的作用，FoxO1a是由AR负调控的转录因子的作用， 在介导非那雄胺和硒的抗癌作用时。目标3：研究（a）激活引发剂 caspase和execution子caspase caspase caspase构成了非那雄胺或硒，或两者兼而有之； （b）是否恢复AR 信号传导逆转了每种药物对caspase激活和caspase介导的凋亡的影响。目标4： 验证非那雄胺/硒的抗癌功效和随附的分子变化 （从目标1到3获得的信息）在人类前列腺癌异种移植模型中。