Prostate Cancer: Targeting Androgen Receptor Signaling by Tetrandrine

前列腺癌：粉防己碱靶向雄激素受体信号传导

• 批准号: 8142602
• 负责人: HARI K KOUL
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142602
• 关键词: Address; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Biological Models; CDKN1A gene; Cancer Cell Growth; Cancer Etiology; Cancer Model; Cell Cycle Arrest; Cell Cycle Inhibition; Cell Cycle Progression; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Data; Development; Diagnosis; Event; Exhibits; Growth; Health; Health education; Human; LNCaP; Libraries; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Messenger RNA; Molecular; Mus; Neoplastic Processes; Normal Cell; Pathway interactions; Phenotype; Play; Population; Prevention; Prostate Cancer therapy; Prostate-Specific Antigen; Proteins; Receptor Signaling; Regulation; Resistance; Role; Screening procedure; Signal Transduction; Stephania tetrandra; Testing; Translating; Tumor Volume; United States; Veterans; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer diagnosis; cell motility; deprivation; effective therapy; efficacy testing; in vivo; inhibitor/antagonist; killings; men; novel; pre-clinical; pre-clinical research; prevent; promoter; receptor binding; research study; response; tumor progression

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.

描述（由申请人提供）： 前列腺癌（PCA）和恶性进展的发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，生长控制损失和免受凋亡的保护。已知AR信号改变在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。这些目标将在三个目的中实现：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； AIM2是定义，表征和建立TET抑制作用对PCA细胞中细胞周期进程和促进凋亡促进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，每年估计有50,000名退伍军人被诊断出患有前列腺癌，每年在退伍军人人口中的前列腺癌死亡约10,000人（基于退伍军人健康教育图书馆和国家前列腺癌联盟）。在本应用中提出的工作将有助于开发一种新型的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大常见的癌症，估计有50,000名退伍军人每年被诊断出患有前列腺癌。前列腺癌每年导致退伍军人人口约10,000人死亡，并且仍然是退伍军人癌症相关死亡的第二大主要原因（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，我们发现四兰（Tet）（TET）有选择地杀死前列腺癌细胞而不会损害正常细胞，部分是通过靶向雄激素受体信号传导。在本应用中提出的工作将有助于开发一种新型的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，因此与退伍军人健康高度相关。