Antitumor Activity & Mechanism of OSW-1 in Pancreatic Ca

抗肿瘤活性

• 批准号: 6719360
• 负责人: Peng Huang
• 金额: $ 15.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719360
• 关键词: antineoplastics; athymic mouse; biological products; cell line; chemical structure function; chemical synthesis; cytotoxicity; drug interactions; drug screening /evaluation; flow cytometry; laboratory mouse; mitochondria; pancreas neoplasms; plant extracts; polymerase chain reaction

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.

描述(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。化疗通常对胰腺癌无效，部分原因是缺乏有效的治疗药物。因此，开发有效的胰腺癌治疗药物是一项紧迫而又至关重要的任务。我们最近的研究表明，OSW-1是一种存在于植物中的天然化合物，对人胰腺癌细胞具有极强的细胞毒活性，体外IC50值小于1 NM，约为目前治疗药物5-FU和吉西他滨的100-1000倍。重要的是，我们证明了与5-FU和吉西他滨不同，5-FU和吉西他滨影响DNA代谢过程，对处于静止期的癌细胞作用有限，而OSW-1的活性涉及线粒体介导的机制，不依赖于细胞周期，在亚纳摩尔浓度范围内有效地杀灭静止期的癌细胞。此外，NFkappaB不能保护胰腺癌细胞免受OSW-1的细胞毒活性的影响，这表明该化合物可能对经常具有NFkappaB结构性激活的人胰腺癌细胞有效。然而，OSW-1发挥作用的确切机制尚不清楚。本探索性/开发性(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，以研究以下特定目的。(1)。检测OSW-1对人胰腺癌细胞株的体外杀伤活性和对荷人胰腺癌细胞小鼠模型的体内治疗活性。(2)。探讨药物作用机制，重点是线粒体在介导OSW-1在胰腺癌细胞中的抗癌活性中的作用。(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。我们期待这项为期两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，并为未来更全面的研究奠定基础。