Antitumor Activity & Mechanism of OSW-1 in Pancreatic Ca

抗肿瘤活性

• 批准号: 6882616
• 负责人: Peng Huang
• 金额: $ 14.69万
• 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/6882616
• 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; 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（由申请人提供）：胰腺癌是最致命的恶性疾病之一，排名第四，是美国癌症死亡的原因。化学疗法通常是由于缺乏有效的治疗剂而对胰腺癌无效。因此，开发有效的胰腺癌治疗剂是紧急且至关重要的任务。我们最近的研究表明，OSW-1是一种天然存在的化合物Orninithogalum Saudersiae，具有针对人类胰腺癌细胞具有极有效的细胞毒性活性，其体外IC50值的价值小于1 nm，比当前的治疗剂5-纤维和珠宝素的效果高约100-1,000倍。重要的是，我们证明了影响DNA代谢过程的5-FU和吉西他滨不同，对静态阶段的癌细胞影响有限，OSW-1的活性涉及一种线粒体介导的机制，与细胞周期无关，并且有效地杀死了亚nan摩尔浓度范围内的quiescent癌细胞。此外，NFKAPPAB不能保护胰腺癌细胞免受OSW-1的细胞毒性活性，这表明该化合物可能对人类胰腺癌细胞有效，而人类胰腺癌细胞经常具有NFKAPPAB的组成型激活。但是，OSW-1发挥作用的确切机制尚不清楚。该探索性/发育性研究项目的主要目标是测试OSW-1对人胰腺癌的抗癌活性，研究药物作用的机制，并确定分子靶标。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方法结合使用，以研究以下特定目的。 （1）。测试OSW-1在体外对人胰腺癌细胞系的细胞毒性活性以及带有人胰腺癌细胞的小鼠模型中体内治疗活性。 （2）。研究药物作用的机制，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）使用蛋白质生物化学和分子生物学方法与新的基因组技术结合使用，确定细胞中OSW-1的分子靶标。我们预计，这个为期两年的探索性研究项目将为OSW-1进一步开发作为有效治疗胰腺癌的潜在药物的重要数据，并作为未来更全面研究的基础。