Tetrandrine for the treatment of Prostate Cancer

粉防己碱用于治疗前列腺癌

• 批准号: 8783637
• 负责人: HARI K KOUL
• 金额: $ 28.28万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783637
• 关键词: Tetrandrine; treatment; Prostate; Cancer

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.

描述（由申请人提供）：在此提案中，我们试图评估四兰氨酸作为对临床前模型系统中前列腺癌的新型靶向剂的功效。已知AR信号改变在前列腺癌以及PCA向castrate抗性表型的进展中起主要作用。在筛选天然化合物以抗前列腺癌细胞生长的作用时，我们发现四兰（TET）对AR阳性PCA细胞具有选择性作用。众所周知，从斯蒂芬氏菌（Stephania Tetrandra）分离出的一种活性成分，它表现出广泛的药理作用，我们是第一个观察其对前列腺癌作用的组。在本应用中提出的初步研究中，当注射小鼠时，我们还观察到了TET，抑制了这些小鼠的人类前列腺癌异种移植物的生长，并大大减少了肿瘤的体积。 TET抑制了前列腺特异性抗原（PSA）的合成和分泌，阻塞了人类PCA细胞在培养中的细胞周期进展和生长，诱导凋亡并抑制细胞迁移和侵袭，这表明该化合物对肿瘤过程产生了直接影响。基于这些令人兴奋的初步数据，我们假设“四链氨基（TET）靶向雄激素受体信号传导，以调节可能相互关联的PCA细胞中的多个分子事件，例如PSA表达，细胞存活和抗凋亡信号传导和抗凋亡信号传导，并导致无需控制的PCA PCA生长和恶性进展涉及涉及的细胞周期。因此，TET可以作为PCA预防，生长控制和治疗的新药物。在当前的提案中，我们将对TET进行基础和临床前研究，以了解针对前列腺癌的作用机理。这些目标将在三个特定目标中实现：目标1是评估TET对前列腺癌细胞中雄激素受体信号传导调节的影响，并研究TET抑制前列腺特异性抗原（PSA）的特定分子机制； AIM 2是定义，表征和建立TET对PCA细胞中细胞周期进程和促进细胞凋亡的抑制作用的分子机制。 AIM 3是评估TET在体内对雄激素反应性和castrate抗性的人PCA细胞衍生的小鼠异种移植模型的疗效。我们预计，提出的研究以及我们的初步数据将确定TET是基于机制的PCA预防，生长控制和治疗的机理药物，并将在临床前的人类PCA细胞衍生的异种移植模型中建立TET的体内TET功效。重要的是要在这里强调，估计在美国，每年有40,000名男性死于前列腺癌。在本应用中提出的工作将有助于开发新的AR靶向疗法，该治疗可能转化为针对前列腺癌的有效治疗团，因此与NCI/NIH的任务高度相关。