Tetrandrine for the treatment of Prostate Cancer

描述（由申请人提供）：在本提案中，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信号的改变在前列腺癌以及前列腺癌向去势抵抗表型的进展中起主要作用。在筛选抗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PCa细胞具有选择性作用。粉防己碱（Tetrandrine, Tet）是从粉防己中分离出来的一种活性成分，具有广泛的药理作用，我们是第一个观察到其对前列腺癌的作用的研究小组。在本申请中提出的初步研究中，我们也观察到，当注射给小鼠时，Tet可以抑制人类前列腺癌异种移植物在这些小鼠中的生长，并显着减少肿瘤体积。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的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具有直接作用。基于这些令人兴奋的初步数据，我们假设“粉防己碱（Tet）靶向雄激素受体信号来调节PCa细胞中的多种分子事件，这些事件可能是相互关联的，例如PSA表达、细胞存活和抗凋亡信号以及不受控制的PCa生长和恶性进展中涉及的细胞周期进展。”因此，Tet可能成为预防、控制前列腺癌生长和治疗前列腺癌的新药物。在目前的提案中，我们将开展Tet的基础和临床前研究，旨在了解Tet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，评估Tet对前列腺癌细胞中雄激素受体信号传导的调节作用，并研究Tet抑制前列腺特异性抗原（PSA）的特定分子机制；目的2：明确、表征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：在体内评估Tet对雄激素反应和去势抵抗的人PCa细胞来源的小鼠异种移植模型的疗效。我们预计，拟议的研究，连同我们的初步数据，将确定Tet作为一种基于机制的药物，用于预防，生长控制和治疗PCA，并将建立Tet在临床前人类PCA细胞衍生异种移植模型中的体内疗效。这里需要强调的是，在美国，每年约有4万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靶向治疗方法，这种治疗方法可能转化为一种有效的前列腺癌治疗方案，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.