Abstract 1705: Bioenergetic changes in glycolysis, Kreb's cycle, and glutaminolysis in pancreatic cells treated with mitochondria-targeted cationic drugs.

Human pancreatic ductal adenocarcinoma (PDAC) is an incurable and highly aggressive human cancer. Current chemotherapy provides a slight increase in survival. New therapeutic strategies to treat PDAC are desperately needed. In this study we used a relatively non-toxic mitochondria-targeted cationic nitroxide (Mito-CP) in combination with antiglycolytic agents (2-deoxyglucose, 2-DG) to selectively inhibit pancreatic cancer cell proliferation. We used high-throughput XF24 extracellular flux analyzer and mass spectrometry-based metabolomics approach to investigate cellular bioenergetics changes in pancreatic cancer cells (MiaPaCa-2 and Panc-1 cells). Results indicate that at nanomolar concentrations, Mito-CP alone potently inhibited proliferation of MiaPaCa-2 cells and synergized with 2-DG in inhibiting intracellular ATP levels. In the presence of glycolytic inhibitors, i.e. 2-DG or 3-bromopyruvate, Mito-CP exhibited enhanced toxicity in both pancreatic cell lines. LC-MS-based metabolomics studies indicate that Mito-CP inhibits Kreb9s cycle metabolites (citric acid, cis-aconitic and isocitric acids) but significantly enhances intracellular glutamine, alpha-ketoglutarate, succinate, fumarate, and malate. This enhancement is abolished in glutamine-free media. We conclude that strategies to modulate bioenergetic metabolism with relatively non-toxic mitochondria-targeted nitroxides in combination with glycolysis or glutaminolysis inhibitors may provide a novel route for treating patients with PDAC with minimal toxic side effects. Citation Format: Gang Cheng, Jacek Zielonka, Joy Joseph, Balaraman Kalyanaraman. Bioenergetic changes in glycolysis, Kreb9s cycle, and glutaminolysis in pancreatic cells treated with mitochondria-targeted cationic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2013-1705