Abstract 1136: Synergistic inhibition of bioenergetic pathways in pancreatic cancer cells by mitochondria-targeted nitroxide and glycolytic inhibitors

Abstract

Abstract Pancreatic adenocarcinoma is one of the most aggressive cancers with a high fatality rate. Currently available chemotherapy for treating pancreatic cancers is ineffective. Emerging research is focused on drugs targeting bioenergetic pathways in tumor cells. Despite decades of evidence that cancer cells have increased aerobic glycolysis, glycolytic inhibition has failed as a chemotherapeutic approach, due in part to enhanced systemic toxicity of antiglycolytic agents. We hypothesized that a combined inhibition of glycolysis and mitochondrial function may represent an alternate therapeutic approach that can potentially overcome the insufficiency of glycolytic inhibition alone. In this study we investigated the chemotherapeutic efficacy of combining mitochondria-targeted nitroxide, Mito-CP (a nitroxide, carboxy proxyl conjugated to a triphenylphosphonium (TPP+) moiety), and inhibitors of glycolysis, 2-deoxy-D-glucose (2-DG) or 3-bromopyruvate (3-BP) in pancreatic cancer cell lines, PANC-1 and MiaPaCa-2. The relative cytotoxicity and mitochondrial bioenergetic changes in pancreatic cancer cells were assessed. We observed that Mito-CP synergized with glycolytic inhibitors (2-DG or 3-BP) in inducing cell death. Using a Seahorse XF24 extracellular flux analyzer, we determined the combined effects of Mito-CP and 2-DG or 3-BP on cellular mitochondrial function and glycolytic function. The combined treatments induced fast and irreversible inhibition of mitochondrial functions and intracellular ATP depletion. Collectively, these results suggest that targeting mitochondrial bioenergetic metabolism with Mito-CP and glycolytic inhibitors such as 2-DG and 3-BP may be a promising chemotherapeutic strategy in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1136. doi:1538-7445.AM2012-1136