Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib

Abstract

Background:Dichloroacetate (DCA), through the inhibition of aerobic glycolysis (the ‘Warburg effect') and promotion of pyruvate oxidation, induces growth reduction in many tumours and is now undergoing several clinical trials. If aerobic glycolysis is active in multiple myeloma (MM) cells, it can be potentially targeted by DCA to induce myeloma growth inhibition.Methods:Representative multiple myeloma cell lines and a myeloma-bearing mice were treated with DCA, alone and in combination with bortezomib.Results:We found that aerobic glycolysis occurs in approximately half of MM cell lines examined, producing on average 1.86-fold more lactate than phorbol myristate acetate stimulated-peripheral blood mononuclear cells and is associated with low-oxidative capacity. Lower doses of DCA (5–10 mℳ) suppressed aerobic glycolysis and improved cellular respiration that was associated with activation of the pyruvate dehydrogenase complex. Higher doses of DCA (10–25 mℳ) induced superoxide production, apoptosis, suppressed proliferation with a G0/1 and G2M phase arrest in MM cell lines. In addition, DCA increased MM cell line sensitivity to bortezomib, and combinatorial treatment of both agents improved the survival of myeloma-bearing mice.Conclusion:Myeloma cells display aerobic glycolysis and DCA may complement clinically used MM therapies to inhibit disease progression.