Poster Presentation 25th Lorne Cancer Conference 2013

Targeting glucose metabolism - a strategy for overcoming drug resistance in breast cancer (#101)

Santhi Achuthan 1 , Anneke C Blackburn 1
  1. Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

The primary hurdle for effective chemotherapy is the inherent or acquired resistance of cancer cells to a variety of anticancer agents. The glycolytic phenotype is one component of the metabolic signature of cancer cells, often referred to as the Warburg effect—high rates of glucose uptake and glycolysis accompanied by lactate production. Recent studies have linked changes in cancer cells’ metabolism to multi-drug resistant phenotype. In the present study we explored whether pharmacological inhibition of glycolysis by dichloroacetate (DCA) can restore drug sensitivity in breast cancer cells.

 MCF7, MDA-MB-231 and T-47D cells were examined for sensitivity to doxorubicin (DOX) (0.1-0.7μM) with and without DCA co-treatment (1-5mM).  DCA did not enhance DOX cytotoxicity.  The cell lines were then selected for DOX resistance by continuous culture in media containing stepwise increases in DOX concentration (0.05-0.7μM) over a period of one month. In contrast to parental cells, co-treatment of DOX-resistant cells with DCA (1mM) enhanced DOX toxicity, restoring sensitivity to a level similar to parental cells. Since DCA inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), we checked the PDK isoform profile in DOX-resistant MDA-MB-231 cells. No increase in PDK expression was found in DOX-resistant cells. DCA treatment markedly increased the intracellular reactive oxygen species (ROS) levels in DOX-resistant cells, suggesting that elevated oxidative stress after DCA treatment enhances cell death. In separate experiments, pre-treatment with DCA for 48hrs (5mM) increased the intracellular concentration of DOX at 48hrs, without any apparent effect on drug uptake at 6hrs. The effect of DCA-induced ROS on cell survival and of DCA on multi-drug transporters in drug resistant cells is currently being investigated. These generic mechanisms give DCA the potential to reverse drug resistance in many cancer settings.