Abstract A90: Dichloroacetate can overcome drug resistance via decreased ABC drug transporter expression and PDK2 inhibition

Abstract

Abstract Introduction: The primary hurdle for effective chemotherapy is the inherent or acquired drug resistance of cancer cells. The glycolytic phenotype (or Warburg effect) is a major metabolic signature of cancer cells. Dichloroacetic acid (DCA) is a non-toxic drug, which can reverse the glycolytic phenotype by inhibiting pyruvate dehydrogenase kinases (PDKs). Recent studies have linked changes in cancer cell metabolism to multi-drug resistance (MDR) phenotypes. We have examined whether reversal of the glycolytic phenotype with DCA can restore sensitivity in drug resistant cancer cells. Methodology: We examined DCA's effects in doxorubicin (DOX)-resistant MDA-MB-231 and MCF7 cells (made by continuous exposure to increasing DOX concentrations for one month) and their DOX-sensitive counterparts by neutral red cell viability assay. Intracellular drug uptake was measured by flow cytometry and expression of PDKs and drug transporters was measured by western blotting. Results: DCA treatment (1mM for 48hrs) significantly (p<0.05) enhanced DOX toxicity in DOX-resistant cells restoring sensitivity to a level similar to parental cells. This is despite DCA having no effect on DOX toxicity in parental cells. PDK2 expression was higher in the drug-selected cells compared to parental cells suggesting the sensitising effect of DCA on drug resistant cells could be an on-target effect. DCA pre-treatment increased the intracellular retention of DOX and mitoxantrone. DCA effectively reduced the expression of ATP-binding cassette (ABC) drug transporters such as P-glycoprotein and ABCG2 in DOX-resistant MDA-MB-231 and MCF7 cells and in vivo in 4T1 mouse mammary tumors. DCA pre-treatment also sensitised the MDR cell line MCF7-FLV1000 towards mitoxantrone induced apoptosis. Conclusion: DCA may be an effective chemo-sensitizing agent in a wide range of MDR cancers, acting by reducing drug transporter expression and inhibiting PDKs. Citation Format: Santhi Achuthan, Richard Callaghan, Anneke C. Blackburn. Dichloroacetate can overcome drug resistance via decreased ABC drug transporter expression and PDK2 inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A90.