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

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.

Mitochondrial targeting by dichloroacetate improves outcome following hemorrhagic shock.

Hemorrhagic shock is a leading cause of death in people under the age of 45 and accounts for almost half of trauma-related deaths. In order to develop a treatment strategy based on potentiating mitochondrial function, we investigated the effect of the orphan drug dichloroacetate (DCA) on survival in an animal model of hemorrhagic shock in the absence of fluid resuscitation. Hemorrhagic shock was induced in rats by withdrawing 60% of the blood volume and maintaining a hypotensive state. The studies demonstrated prolonged survival of rats subjected to hemorrhagic injury (HI) when treated with DCA. In separate experiments, using a fluid resuscitation model we studied mitochondrial functional alterations and changes in metabolic networks connected to mitochondria following HI and treatment with DCA. DCA treatment restored cardiac mitochondrial membrane potential and tissue ATP in the rats following HI. Treatment with DCA resulted in normalization of several metabolic and molecular parameters including plasma lactate and p-AMPK/AMPK, as well as Ach-mediated vascular relaxation. In conclusion we demonstrate that DCA can be successfully used in the treatment of hemorrhagic shock in the absence of fluid resuscitation; therefore DCA may be a good candidate in prolonged field care following severe blood loss.

Two mixed-NH3/amine platinum (II) anticancer complexes featuring a dichloroacetate moiety in the leaving group.

Two mixed-NH3/amine platinum (II) complexes of 3-dichoroacetoxylcyclobutane-1, 1-dicarboxylate have been prepared in the present study and characterized by elemental analysis and IR, HPLC-MS and (1)H, (13)C-NMR. The complexes exist in equilibrium between two position isomeric forms and undergo hydrolysis reaction in aqueous solution, releasing the platinum pharmacophores and dichloroacetate which is a small-molecular cell apoptosis inducer. Both complexes were evaluated for in vitro cytotoxic profile in A549, SGC-7901 and SK-OV-3 cancer cells as well as in BEAS-2B normal cells. They exhibit markedly cytotoxicity toward cancer cells by selectively inducing the apoptosis of cancer cells, whereas leaving normal cells less affected. They have also the ability to overcome the resistance of SK-OV-3 cancer cells to cisplatin. Our findings offer an alternative novel way to develop platinum drugs which can both overcome the drug resistance and selectively target tumor cells.