Antitumor Activity & Mechanism of OSW-1 in Pancreatic Ca

描述（由申请人提供）：胰腺癌是最致命的恶性疾病之一，在美国癌症死亡原因中排名第四。由于缺乏有效的治疗药物，化疗通常对胰腺癌无效。因此，开发有效的胰腺癌治疗药物是一项紧迫而重要的任务。我们最近的研究表明，OSW-1是一种天然存在于植物Orninithogalum saudersiae中的化合物，对人胰腺癌细胞具有非常有效的细胞毒活性，其体外IC50值小于1 nM，比目前的治疗剂5-FU和吉西他滨强约100- 1000倍。重要的是，我们证明了与5- FU和吉西他滨不同，OSW-1的活性涉及线粒体介导的机制，不依赖于细胞周期，并且在亚纳摩尔浓度范围内有效杀死静止的癌细胞。此外，NFkappaB不能保护胰腺癌细胞免受OSW-1的细胞毒活性，这表明该化合物可能对人类胰腺癌细胞有效，因为胰腺癌细胞经常具有NFkappaB的组成性激活。然而，OSW-1发挥其作用的确切机制尚不清楚。本探索性/发展性（R21）研究项目的主要目的是检测OSW-1对人胰腺癌的抗癌活性，探讨其药物作用机制，并确定其分子靶点。包括生化和分子生物学方法在内的多种实验方法将与线粒体遗传学方法相结合，以研究以下具体目标。(1)。体外检测OSW-1对人胰腺癌细胞系的细胞毒活性，并在携带人胰腺癌细胞的小鼠模型上检测其体内治疗活性。(2)。探讨药物作用机制，重点研究线粒体在介导胰腺癌细胞OSW-1抗癌活性中的作用。(3)利用蛋白质生物化学和分子生物学方法，结合新的基因组技术，确定OSW-1在细胞中的分子靶点。我们期待这个为期2年的探索性研究项目将为进一步开发OSW-1作为有效治疗胰腺癌的潜在候选药物提供重要数据，并为今后更全面的研究奠定基础。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most deadly malignant disease and ranks fourth as a cause of death from cancer the United States. Chemotherapy is usually ineffective for pancreatic cancer due in part to the lack of effective therapeutic agents. Thus, the development of effective therapeutic agents for pancreatic cancer is an urgent and vitally important task. Our recent study indicates that OSW-1, a naturally occurring compound present in a plant, Orninithogalum saudersiae, possesses an extremely potent cytotoxic activity against human pancreatic cancer cells with an in vitro IC50 value of less than 1 nM, approximately 100-1,000 times more potent than the current therapeutic agents 5-FU and gemcitabine. Importantly, we demonstrated that unlike 5- FU and gemcitabine, which affect DNA metabolic process and has limited effect on cancer cells in quiescent stage, the activity of OSW-1 involves a mitochondria-mediated mechanism, is independent of cell cycle, and effectively kills quiescent cancer cells at the sub-nanomolar concentration range. Furthermore, NFkappaB does not protect pancreatic cancer cells from the cytotoxic activity of OSW-1, suggesting that this compound may be effective against human pancreatic cancer cells, which frequently have a constitutive activation of NFkappaB. However, the exact mechanism by which OSW-1 exerts its effect remains unclear. The main objectives of this exploratory/developmental (R21) research project are to test the anticancer activity of OSW-1 against human pancreatic cancer, to investigate the mechanism of the drug action, and to identify the molecular target. Multiple experimental approaches including biochemical & molecular biology methods will be combined with mitochondrial genetic approaches to investigate the following specific aims. (1). Test the cytotoxic activity of OSW-1 in vitro against human pancreatic cancer cell lines and the in vivo therapeutic activity in mouse models bearing human pancreatic cancer cells. (2). Investigate the mechanism of drug action, focusing on the role of mitochondria in mediating the anticancer activity of OSW-1 in pancreatic cancer cells. (3) Identify the molecular target of OSW-1 in the cells, using protein biochemistry and molecular biology methods in combination with new genomic technology. We anticipate that this 2-year exploratory research project will provide important data for further development of OSW-1 as a potential drug candidate for effective treatment of pancreatic cancer, and serves as a basis for more comprehensive studies in the future.