Translational Research of Finasteride and Selenium Prevention of Prostate Cancer

描述(由申请人提供)：该计划项目的目标是开发一种新的机制驱动的前列腺癌预防策略。该方法的基础是通过使用非那雄胺抑制双氢睾酮的形成和使用硒减少雄激素受体(AR)的表达来同时在两个不同的步骤抑制雄激素信号转导。该计划是按照从长椅到床边的模式建立的，由三个高度整合的项目组成。项目1描述了非那雄胺和硒如何协同作用来调节某些分子事件，以控制前列腺癌细胞的克隆性扩张。特别强调了对非那雄胺/硒治疗后诱导细胞凋亡的关键靶点和途径的功能分析。由于血管系统的异常，微环境缺氧常见于一群增殖的癌细胞。众所周知，低氧会产生多种分子变化，作为一种选择性生存压力。最近的证据表明，低氧促进了AR的激活和雄激素反应基因的转录。上述过程是由一种名为过氧化还蛋白-1或PRX1的氧化还原调节蛋白介导的。PRX1在前列腺上皮内瘤变和前列腺癌细胞中优先升高。第二个项目是研究低氧/PRXL刺激AR信号的机制，并评估PRX1在改变非那雄胺/硒的癌症控制效果中的作用。项目1和项目2的发现对于解释项目3的临床试验结果至关重要。我们提出了一项短期干预试验，以验证非那雄胺/硒对前列腺术前患者前列腺组织中雄激素靶基因表达和诱导细胞凋亡的影响。该试验的第二个目标是确定高水平的PRX1是否降低了对非那雄胺/硒干预的敏感性。在美国，每年约有23万新确诊的前列腺癌病例，约3万名男性将死于这种疾病。作为一个公共卫生问题，前列腺癌产生了巨大的医疗保健和人类痛苦的成本。阻止小体积、低级别肿瘤的进展越来越被认为是前列腺癌控制的一个重要方面。我们的目标是找到一种在早期阶段管理疾病的方法，以防止它变得与临床相关。

DESCRIPTION (provided by applicant): The objective of the program project is to develop a novel mechanism-driven strategy for prostate cancer prevention. The approach is based on suppressing androgen signal transduction at two different steps simultaneously by using finasteride to inhibit the formation of dihydrotestosterone and selenium to reduce androgen receptor (AR) expression. The program is built along a bench-to-bedside paradigm and consists of three highly integrated projects. Project 1 is to delineate how finasteride and selenium work cooperatively to modulate certain molecular events in controlling the clonal expansion of prostate cancer cells. Special emphasis is placed on the functional analysis of key targets and pathways responsible for the induction of apoptosis following treatment with finasteride/selenium. Microenvironmental hypoxia is frequently seen in a colony of proliferating cancer cells due to abnormalities of the vasculature. It is well known that hypoxia produces a variety of molecular changes as a selective pressure for survival. There is recent evidence suggesting that hypoxia facilitates AR activation and the transcription of androgen-responsive genes. The above process is mediated by a redox-regulating protein called peroxiredoxin-1, or Prx1. Prx1 is preferentially elevated in prostatic intraepithelial neoplasia and prostate cancer cells. Project 2 is to investigate the mechanism of hypoxia/Prxl stimulation of AR signaling and to assess the role of Prx1 in modifying the cancer control efficacy of finasteride/selenium. The findings of Projects 1 and 2 are critical to the interpretation of the clinical trial results of Project 3. A short-term intervention trial is proposed to verify the effect of finasteride/selenium on androgen target gene expression and apoptosis induction in prostate tissue samples obtained from pre-prostatectomy patients. A second objective of the trial is to determine whether a high level of Prx1 diminishes the sensitivity to finasteride/selenium intervention. Every year, approximately 230,000 new cases of prostate cancer are diagnosed in the US, and some 30,000 men will die of this disease. As a public health problem, prostate cancer engenders huge medical care and human suffering costs. Blocking the progression of small volume, low-grade neoplasia is increasingly being recognized as an important aspect of prostate cancer control. Our goal is to find a way of managing the disease at an early stage in order to prevent it from becoming clinical relevant.