Antitumor Activity & Mechanism of OSW-1 in Pancreatic Ca

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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.