Evidence from population studies suggests that phytochemicals in fruits and vegetables provide aprotective effect against cancer including pancreatic cancer. The majority of cancer patients besidestraditional 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 greatimportance 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 foodsand nutritional supplements.We have recently demonstrated that both growth factors and extracellular matrix proteins activateprosurvival pathways in pancreatic cancer cells through their ability to activate systems that generatereactive oxygen species (ROS). Further, we have determined that the pancreatic stellate cell, the cellresponsible for fibrosis and inflammation in chronic pancreatitis and the desmoplastic reaction of pancreaticadenocarcinoma, 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 toboth 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 weconsidered the possibility that ROS are necessary in these proliferative cells because they regulate thepentose cycle pathways which, in turn, are necessary for the production of ribose and deoxyribose for thesynthesis 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 andcancer cells; and further to determine the role that their inhibition of ROS production plays in regulation ofthis phenotype. We will use this information to design experiments to test the phytochemicals for preventionand/or treatment of the two disorders of the exocrine pancreas involving proliferative disorders of stellate andcancer cells-chronic pancreatitis and pancreatic cancer using experimental animal models.
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