Prostate Cancer: Targeting Androgen Receptor Signaling by Tetrandrine

描述（由申请人提供）： 前列腺癌（PCa）的发展和恶性进展需要改变许多细胞过程的调节，这些过程可能是相互关联的，包括雄激素受体（AR）信号传导，生长控制的丧失和细胞凋亡的保护。已知改变的AR信号传导在PCa向去势抗性表型的进展中起主要作用。在筛选天然化合物对前列腺癌细胞生长的影响时，我们发现粉防己碱（泰特）对AR阳性PCa细胞具有选择性作用。汉防己甲素（泰特）是从粉防己中分离得到的一种活性成分，具有广泛的药理作用，我们是第一个观察其抗前列腺癌作用的研究小组。在本申请中提出的初步研究中，我们还观察到泰特在注射到小鼠中时抑制这些小鼠中的人前列腺癌异种移植物的生长，并显著减小肿瘤体积。泰特抑制前列腺特异性抗原（PSA）的合成和分泌，阻断培养的人PCa细胞的细胞周期进程和生长，诱导细胞凋亡，并抑制细胞迁移和侵袭，表明该化合物对肿瘤过程的直接影响。基于这些令人兴奋的初步数据，我们假设粉防己碱（泰特）靶向雄激素受体信号传导以调节PCa细胞中可能相互关联的多种分子事件，例如PSA表达、细胞存活和抗凋亡信号传导以及参与不受控制的PCa生长和恶性进展的失调的细胞周期进程。“因此，泰特可以作为预防、控制和治疗前列腺癌的新药物。在目前的提案中，我们将对泰特进行基础和临床前研究，目的是了解其对前列腺癌的作用机制。本研究的主要目的有三个：目的1，评价泰特对前列腺癌细胞雄激素受体信号转导的影响，研究泰特抑制前列腺特异性抗原（PSA）的分子机制;目的2，明确、表征和建立泰特抑制前列腺癌细胞周期进程和促进前列腺癌细胞凋亡的分子机制。目的3，评价泰特对雄激素敏感和去势抵抗的人前列腺癌细胞来源的小鼠异种移植模型的体内疗效。我们预计，所提出的研究，连同我们的初步数据，将确定泰特作为一个基于机制的代理，用于预防，生长控制和治疗PCA，并将建立体内疗效的泰特在临床前人类PCa细胞衍生的异种移植模型。值得强调的是，估计每年有50，000名退伍军人被诊断患有前列腺癌，每年约有10，000名退伍军人死于前列腺癌（基于退伍军人健康教育图书馆和国家前列腺癌联盟）。本申请中提出的工作将有助于开发一种新型AR靶向治疗，该治疗可能转化为针对前列腺癌的有效治疗方案，因此与退伍军人健康高度相关。 公共卫生相关性： 前列腺癌（PCa）是美国男性中诊断出的最常见的癌症，也是癌症死亡的第二大原因。前列腺癌是退伍军人中第二常见的癌症，估计每年有5万名退伍军人被诊断患有前列腺癌。前列腺癌每年导致约10，000名退伍军人死亡，并且仍然是退伍军人癌症相关死亡的第二大原因（基于退伍军人健康教育图书馆和国家前列腺癌联盟）。在我们令人兴奋的初步研究中，我们发现粉防己碱（泰特）选择性地杀死前列腺癌细胞而不伤害正常细胞，部分原因是通过靶向雄激素受体信号传导。本申请中提出的工作将有助于开发一种新型AR靶向治疗，该治疗可能转化为针对前列腺癌的有效治疗方案，因此与退伍军人健康高度相关。

DESCRIPTION (provided by applicant): Development of prostate cancer (PCa) and malignant progression requires altered regulation of many cellular processes, which are probably interrelated, including androgen receptor (AR) signaling, loss of growth control, and protection from apoptosis. Altered AR signaling is known to play a major role in progression of PCa to Castrate resistant phenotype. While screening for natural compounds for effects against prostate cancer cell growth, we found tetrandrine (Tet) to have selective effects against AR positive PCa cells. Tetrandrine (Tet), an active ingredient isolated from Stephania tetrandra is known to exhibit a broad range of pharmacological actions, and we are the first group to observe its effects against prostate cancer. In preliminary studies presented in this application, we also observed Tet, when injected to mice inhibited the growth of human prostate cancer xenografts in these mice, and dramatically decreased tumor volume. Tet inhibited Prostate Specific Antigen (PSA) synthesis and secretion, blocked cell cycle progression and growth of human PCa cells in culture, induced apoptosis, and inhibited cell migration and invasion, suggesting a direct effect of this compound on the neoplastic process. Based on these exciting preliminary data we hypothesize that "Tetrandrine (Tet) targets Androgen Receptor signaling to modulate multiple molecular events in PCa cells that are probably interrelated, such as PSA expression, cell survival and anti-apoptotic signaling and deregulated cell cycle progression involved in uncontrolled PCa growth and malignant progression." As such, Tet may serve as a novel agent for prevention, growth control and therapy of PCa. In the current proposal we will conduct basic and pre-clinical research on Tet with an aim to understand the mechanisms of action against prostate cancer. These objectives will be achieved in three Aims: Aim 1, is to evaluate the effects of Tet on modulation of Androgen Receptor signaling in prostate cancer cells and to study specific molecular mechanisms by which Tet inhibits Prostate Specific Antigen (PSA); Aim2, is to define, characterize, and establish molecular mechanism of the inhibitory effect of Tet on cell cycle progression and promotion of apoptosis in PCa cells.; Aim 3, is to evaluate efficacy of Tet against androgen responsive and castrate resistant human PCa cell derived mouse Xenograft models in vivo. We anticipate that proposed studies, together with our preliminary data, will identify Tet as a mechanism-based agent for the prevention, growth control and therapy of PCA, and will establish in vivo efficacy of Tet in pre-clinical human PCa cell derived xenograft models. It is important to emphasize here that an estimated 50,000 veterans being diagnosed with Prostate cancer every year and about 10,000 deaths result from prostate cancer in veteran population each year (based on Veterans Health education library and the National Prostate Cancer Coalition). Work proposed in this application, will contribute to development of a novel AR targeted therapy that may translate into an effective treatment regiment against prostate cancer and is therefore, highly relevant to Veteran health. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the most common cancer diagnosed and the second leading cause of cancer death in men in the United States. Prostate cancer is the second most common cancer in veterans, with an estimated 50,000 veterans being diagnosed with prostate cancer every year. Prostate cancer results in about 10,000 deaths in veteran population each year and remains the second leading cause of cancer-associated deaths in veterans (based on Veterans Health education library and the National Prostate Cancer Coalition). In our exciting preliminary studies we discovered that Tetrandrine (Tet) selectively killed prostate cancer cells without harming normal cells, in part by targeting Androgen Receptor signaling. Work proposed in this application, will contribute to development of a novel AR targeted therapy that may translate into an effective treatment regiment against prostate cancer and is therefore, highly relevant to Veteran health.