Polyphenols Regulate Lipid Inflamm Processes in Pancreatic Cancer/Harris, Diane

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Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States. At the time of diagnosis most patients have metastatic disease and despite attempts to employ unique combination therapies the 5-year survival remains 4%. Although important progress has been made in understanding its biology, this knowledge has not yet resulted in a substantial change in patient survival and there is clearly a need to develop new and better strategies for the treatment of PDA. Inflammatory processes are instrumental to carcinogenesis and cancer progression. Eicosanoids, formed by cyclooxygenase and lipoxygenase activity, are important bioactive lipids produced in inflammatory and neoplastic conditions. Inhibition of eicosanoid production reduces the incidence and diminishes the progression of human cancers. Polyphenolic compounds from food sources and dietary supplements have been shown to possess anti-inflammatory properties via inhibition of cyclooxygenase and/or lipoxygenase activity. Based on data from our preliminary and the available literature, we hypothesize that polyphenolic compounds from green tea and Scutellaria baicalensis (SB): 1) inhibit proliferation and eicosanoid production in PDA cells; 2) lower the risk of developing PDA (preventive effect); and, 3) reduce the growth and spread of established PDA (therapeutic effect). We will study mechanisms of green tea (polyphenon E) and SB polyphenol action on proliferation, apoptosis, and cell cycle regulation in vitro as well as using stable isotopebased dynamic metabolic profiling (SIDMAP) technology to evaluate the overall phenotypic effect of polyphenols on PDA cells. In addition we will use mouse models to determine if polyphenon E and SB on can inhibit pancreatic carcinogenesis in a transgenic model of PDA (prevention model) and reduce PDA cell growth in the orthotopic xenograft model (treatment model). A unique aspect of our proposal is to use stable isotope-based metabolomics approach to relate changes in metabolic flux occuring at different stages in the carcinogenisis process in the transgenic mice. Our findings will form the rationale for future dietary recommendations involving phytonutrients and provide the scientific background for developing clinical trials designed to evaluate the potentially therapeutic and preventive benefit of polyphenolic compounds from green tea, SB, and other botanicals in PDA.