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: 8305421
• 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/8305421
• 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.

描述（由申请人提供）： 前列腺癌 (PCa) 的发生和恶性进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、生长控制丧失和细胞凋亡保护。已知 AR 信号传导的改变在前列腺癌向去势抵抗表型的进展中发挥着重要作用。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 (Tet) 对 AR 阳性 PCa 细胞具有选择性作用。粉防己碱 (Tet) 是一种从粉防己中分离出来的活性成分，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。在本申请提出的初步研究中，我们还观察到，当注射到小鼠体内时，Tet 会抑制这些小鼠体内人类前列腺癌异种移植物的生长，并显着减小肿瘤体积。 Tet 抑制前列腺特异性抗原 (PSA) 的合成和分泌，阻断培养中人 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有直接影响。基于这些令人兴奋的初步数据，我们假设“粉防己碱 (Tet) 以雄激素受体信号传导为目标，调节 PCa 细胞中可能相互关联的多个分子事件，例如 PSA 表达、细胞存活和抗凋亡信号传导，以及与不受控制的 PCa 生长和恶性进展相关的细胞周期进程失调。”因此，Tet 可以作为预防、控制生长和治疗 PCa 的新型药物。在当前的提案中，我们将对 Tet 进行基础和临床前研究，旨在了解其对抗前列腺癌的作用机制。这些目标将通过三个目标来实现：目标1，评估Tet对前列腺癌细胞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）的具体分子机制；目的2，定义、表征和建立Tet对PCa细胞的细胞周期进程和促进细胞凋亡的抑制作用的分子机制。目标 3 是在体内评估 Tet 对雄激素反应性和去势抵抗性人 PCa 细胞衍生的小鼠异种移植模型的功效。我们预计，拟议的研究连同我们的初步数据将确定 Tet 作为预防、生长控制和治疗 PCA 的基于机制的药物，并将在临床前人类 PCa 细胞异种移植模型中确定 Tet 的体内功效。这里需要强调的是，每年估计有 50,000 名退伍军人被诊断患有前列腺癌，每年约有 10,000 名退伍军人死于前列腺癌（根据退伍军人健康教育图书馆和国家前列腺癌联盟）。本申请中提出的工作将有助于开发一种新型 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，因此与退伍军人健康高度相关。