Phytochemicals & Metabolism in Pancreatic Diseases/Pandol, Stephen

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Evidence from population studies suggests that phytochemicals in fruits and vegetables provide a protective effect against cancer including pancreatic cancer. The majority of cancer patients besides traditional treatments also use natural non-prescription cancer drugs, of which, most are of plant origin. Therefore, the mechanistic understanding of potential benefits of phytochemicals would be of great importance in prevention of pancreatic cancer as well as disorders that increase the risk of pancreatic cancer (i.e. chronic pancreatitis) by identifying target pathways and beneficial effects of these molecules in foods and nutritional supplements. We have recently demonstrated that both growth factors and extracellular matrix proteins activate prosurvival pathways in pancreatic cancer cells through their ability to activate systems that generate reactive oxygen species (ROS). Further, we have determined that the pancreatic stellate cell, the cell responsible for fibrosis and inflammation in chronic pancreatitis and the desmoplastic reaction of pancreatic adenocarcinoma, also uses the production of ROS to mediate proliferation with growth factor stimulation. In preliminary data we show that selected phytochemicals (rottlerin, ellagic acid, embelin, lycopene) act to both attenuate the production of ROS in pancreatic cancer and stellate cells and inhibit their DMA synthesis. To initiate investigations into the mechanisms underlying the antiproliferative effects of these molecules we considered the possibility that ROS are necessary in these proliferative cells because they regulate the pentose cycle pathways which, in turn, are necessary for the production of ribose and deoxyribose for the synthesis of nucleic acids. We provide preliminary metabolomic data to support this hypothesis. The experiments in this project are designed to test the effect of each of rottlerin, ellagic acid, embelin, curcumin and lycopene on regulating the proliferative metabolic phenotype of the pancreatic stellate and cancer cells; and further to determine the role that their inhibition of ROS production plays in regulation of this phenotype. We will use this information to design experiments to test the phytochemicals for prevention and/or treatment of the two disorders of the exocrine pancreas involving proliferative disorders of stellate and cancer cells-chronic pancreatitis and pancreatic cancer using experimental animal models.