Tetrandrine for the treatment of Prostate Cancer

描述(由申请人提供)：在这项提案中，我们寻求在临床前模型系统中评估粉防己碱作为一种新型靶向药物治疗前列腺癌的疗效。已知AR信号改变在前列腺癌以及前列腺癌向去势耐药表型的进展中发挥重要作用。在筛选抑制前列腺癌细胞生长的天然化合物时，我们发现粉防己碱(Tet)对AR阳性的前列腺癌细胞具有选择性作用。粉防己碱(Tet)是从粉防己中分离出来的一种活性成分，已知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小组。在这项应用中提出的初步研究中，我们还观察到，当Tet注射到小鼠体内时，可以抑制这些小鼠的人前列腺癌异种移植瘤的生长，并显著减少肿瘤体积。Tet抑制前列腺特异性抗原(PSA)的合成和分泌，阻断培养的人前列腺癌细胞周期进程和生长，诱导细胞凋亡，抑制细胞迁移和侵袭，提示该化合物在肿瘤过程中有直接作用。基于这些令人振奋的初步数据，我们假设“粉防己碱(Tet)以雄激素受体信号为靶点，调节PCa细胞中可能相互关联的多个分子事件，如PSA表达、细胞存活和抗凋亡信号，以及参与失控的PCa生长和恶性进展的细胞周期失控进展。”因此，Tet可能成为预防、控制和治疗前列腺癌的一种新的药物。在目前的提案中，我们将对Tet进行基础和临床前研究，以期了解其抗前列腺癌的作用机制。目的1，评价Tet对前列腺癌雄激素受体信号转导的调节作用，研究Tet抑制前列腺特异性抗原(PSA)的分子机制；目的2，定义、表征和建立Tet抑制前列腺癌细胞周期进程和促进细胞凋亡的分子机制。目的3，体内评价Tet对雄激素反应性和去势耐受的人前列腺癌细胞来源的异种移植模型的疗效。我们预计，与我们的初步数据一起，拟议的研究将确定Tet是预防、生长控制和治疗PCa的一种基于机制的药物，并将在临床前人类PCa细胞来源的异种移植模型中建立Tet的体内疗效。这里需要强调的是，据估计，美国每年有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的AR靶向疗法，该疗法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)是美国最常见的癌症，也是男性癌症死亡的第二大原因。前列腺癌是男性第二常见的癌症，据估计，美国每年有25万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4万人死亡，仍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(Tet)选择性地杀死前列腺癌细胞，而不损害正常细胞，部分是通过靶向雄激素受体信号。本申请中提出的工作将有助于开发一种新的AR靶向疗法，该疗法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.