W1393 Is Tumor M2-Pyruvate Kinase (PK) a Potential Marker for the Discrimination Between Chronic Pancreatitis and Pancreatic Cancer?

Abstract

were determined. MIA PaCa-2 pancreatic cancer cell lines with functional mitochondria (rho+) and the same lines without functional mitochondria (rhoo) (J. Biol. Chem. 281:37416, 2006), were treated with ascorbate and clonogenic survival determined. The oxygen electrode method was used to determine H2O2 production. MIA PaCa-2 tumor cells (2 x 106) were delivered subcutaneously into the flank region of nude mice and allowed to grow until they reached 3 mm in greatest dimension at which time they were randomized to receive either ascorbate (4g/kg) or osmotically equivalent i.p. saline as a control (1 M) given to mice i.p. every day for two weeks. Results: There was a time and dose-dependent increase in measured H2O2 productionwith increased concentrations of ascorbate. Ascorbate decreased clonogenic survival and viability in pancreatic cancer cell lines in a dose-dependent manner. Ascorbate had no effect on the H6c7 cell line, but decreased viability in the H6c7 cell lines that express K-ras oncogene. Ascorbate (5 and 10 mM) decreased viability in all human pancreatic cancer cell lines tested. In rho+ cells, ascorbate resulted in a dose-dependent decrease in clonogenic survival, but no cytotoxicity in the rhoo cells. The group of animals that received ascorbate had significantly slower tumor growth when compared to the controls receiving osmotically equivalent saline (P < 0.0001, n = 5-8/group). On day 15 of treatment, there was a 3.5fold decrease in tumor growth in animals receiving ascorbate when compared to controls. Conclusions: Pharmacological doses of ascorbate, achievable in humans when given intravenously, may have potential for therapy in pancreatic cancer. The ascorbate-induced cytotoxicity in pancreatic cancer cells may be mediated by a mitochondrial mechanism.