Tetrandrine for the treatment of Prostate Cancer

描述（由申请人提供）：在本提案中，我们试图在临床前模型系统中评估粉防己碱作为新型靶向药物对前列腺癌的疗效。已知改变的AR信号传导在前列腺癌以及PCa进展为去势抵抗表型中起主要作用。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。这些目标将在三个具体目标中实现：目标1，是评价泰特对前列腺癌细胞中雄激素受体信号转导的调节作用，并研究泰特抑制前列腺特异性抗原（PSA）的特定分子机制;目标2，是定义、表征和建立泰特抑制前列腺癌细胞周期进展和促进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。在此需要强调的是，美国每年估计有40，000名男性死于前列腺癌。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NCI/NIH的使命高度相关。 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。前列腺癌是男性中第二常见的癌症，在美国每年估计有250，000名男性被诊断患有前列腺癌。前列腺癌每年导致美国人口约40，000人死亡，并且仍然是癌症相关死亡的第二大原因。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NCI/NIH的使命高度相关。

DESCRIPTION (provided by applicant): In this proposal we seek to evaluate efficacy of tetrandrine as a novel targeted agent against prostate cancer in pre-clinical model systems. Altered AR signaling is known to play a major role in prostate cancer as well as 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 specific 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); Aim 2, 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 40,000 men die of Prostate cancer every year in the US. 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 the mission of NCI/NIH. 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 men, with an estimated 250,000 men being diagnosed with prostate cancer in the US every year. Prostate cancer results in about 40,000 deaths in US population each year and remains the second leading cause of cancer-associated deaths. 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 the mission of NCI/NIH.