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)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、生长控制的丧失和对细胞凋亡的保护。已知AR信号的改变在PCa向去势耐药表型的进展中起主要作用。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；AIM2，定义、表征和建立Tet抑制PCa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PCa细胞来源的小鼠移植瘤的疗效。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。这里必须强调的是，据估计，每年有50,000名退伍军人被诊断患有前列腺癌，退伍军人中每年约有10,000人死于前列腺癌(根据退伍军人健康教育图书馆和全国前列腺癌联盟)。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。前列腺癌是退伍军人中第二常见的癌症，据估计，每年有5万名退伍军人被诊断患有前列腺癌。前列腺癌每年在退伍军人中造成约10,000人死亡，仍然是退伍军人癌症相关死亡的第二大原因(根据退伍军人健康教育图书馆和全国前列腺癌联盟)。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，与退伍军人健康高度相关。