Targeting prostate cancer by inhibition of mTOR with ezhu oil

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的第三大原因。前列腺癌的常见治疗，激素消融和内分泌治疗，导致暂时缓解。其他新的雄激素受体以外的分子靶点的发现将有助于开发新的有效的治疗药物。分子遗传学研究发现，PI 3 K/Akt/mTOR信号通路介导细胞增殖和存活，在前列腺癌中被激活。mTOR信号传导是开发用于治疗前列腺癌的治疗剂的主要靶标。莪术油是从姜黄中提取的精油，已被用作治疗病毒感染和癌症的传统中药。莪术油及其成分之一莪术醇抑制前列腺癌细胞生长和mTOR信号通路。我们假设可能含有新型mTOR信号传导抑制剂的莪术油可用作治疗剂或与已知的mTOR抑制剂雷帕霉素类似物CCI-779组合作为前列腺癌治疗的补充治疗药物。我们建议1）：鉴定抑制mTOR信号传导的莪术油的活性成分，并基于活性成分标准化莪术油; 2）：研究mTOR信号传导途径在莪术油和姜黄素抑制的前列腺癌细胞生长中的作用，并确定莪术油或姜黄素与CCI-779在前列腺癌细胞中的联合作用; 3）确定莪术油和莪术醇单独或与CCI-779组合在异种移植物中的体内功效。我们希望我们的应用将导致发现一种新的补充剂前列腺癌治疗的基础上的特定分子靶点。 公共卫生相关性：本研究旨在探讨中药莪术油的生长抑制作用，并对其作用机制和活性成分进行鉴定。本申请的目的是希望建立一个合理的，以改善治疗结果的补充和替代药物的基础上，特定的分子靶点在前列腺癌。

DESCRIPTION (provided by applicant): Prostate cancer is the third leading cause of cancer death of males in the United States. The common treatments for prostate cancer, hormone ablation and endocrine therapy, lead to temporary palliation. Identification of other novel molecular targets independent of androgen receptor would lead to the development of new effective therapeutic agents. Advances in molecular genetics have identified that PI3K/Akt/mTOR signaling pathway mediates cellular proliferation and survival and that is activated in prostate cancer. The mTOR signaling is a prime target for development of therapeutic agents for treating prostate cancer. Ezhu oil, the essential oil isolated from Curcuma, has been used as a traditional Chinese medicine to treat virus infections and cancers. Ezhu oil and one of its components, curcumol, inhibit prostate cancer cell growth and the mTOR-signaling pathway. We hypothesize that ezhu oil which might contain novel mTOR signaling inhibitors could be used as a therapeutic agent or in combination with known mTOR inhibitor rapamycin analogue CCI-779 as a complementary therapeutic medicine for prostate cancer treatment. We propose 1): to identify the active components of ezhu oil which inhibit mTOR signaling and to standardize ezhu oil based on the active component(s); 2): to investigate the roles of the mTOR signaling pathway in ezhu oil- and curcumol-inhibited prostate cancer cell growth and to determine the combined effects of ezhu oil or curcumol with CCI-779 in prostate cancer cells; 3) to determine the efficacies of ezhu oil and curcumol alone or in combination with CCI-779 in vivo in xenografts. We hope our application will lead to the discovery of a novel complementary agent for prostate cancer treatment based on the specific molecular targets. PUBLIC HEALTH RELEVANCE: This application will investigate the growth inhibitory effect of ezhu oil, a traditional Chinese medicine, and to identify the mechanism of action and the active components. The purpose of this application hopes to establish a rational for improving the therapeutic outcome of complementary and alternative medicines based on specific molecular targets in prostate cancer.