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

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

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