Poster Presentation 2nd Australian Cancer and Metabolism Meeting 2017

Dichloroacetate at clinically achievable concentrations can reduce pPDH and reverse the glycolytic phenotype in multiple myeloma cells (#57)

Dan Dan Tian 1 , Anneke C Blackburn 1
  1. ACRF Dept Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia

Multiple myeloma (MM) is a B-cell malignancy with a glycolytic phenotype. Dichloroacetate (DCA) is a pyruvate dehydrogenase (PDH) kinase (PDK) inhibitor that can reverse the glycolytic phenotype. In vitro, DCA (≥10mM) inhibited MM proliferation and induced apoptosis, but these concentrations are above those clinically achievable and are likely acting off-target. We examined whether DCA at clinically achievable levels can act on target, inhibit MM cell growth and enhance effects of other drugs.

The response of five human MM cell lines to DCA alone or combined with nutrient deprivation, hypoxia, 2-deoxyglucose, dexamethasone or orlistat was measured using neutral red viability assay. pPDH/tPDH was measured by western blotting. PDK expression was measured by rt-PCR and western blotting. Cell proliferation (CFSE), cell cycle (BrdU/PI) and apoptosis (Annexin V/7AAD) were measured by FACS.

DCA (1-5mM) decreased cell proliferation without increasing apoptosis or inducing cell cycle arrest. This was accompanied by decreased pPDH and lactate which were dependent on the presence of glucose. DCA treatment as low as 0.1-0.3mM decreased pPDH/tPDH within 5-24hr. These concentrations are based on DCA serum peak and trough levels in MM patients in our DiCAM clinical trial (1). DCA had a greater effect on growth inhibition under hypoxia, corresponding with induction of the target PDKs. DCA combined with dexamethasone (inhibits glycolysis) or orlistat (fatty acid synthase inhibitor) had additive effects in reducing viable cells, and were accompanied by greater changes in metabolism.

DCA can act on target in MM cells at clinically achievable levels and may be a useful therapy in combination with other low toxicity metabolism modifying drugs.

  1. (1) DiCAM (DiChloroAcetate in Myeloma): a trial of dichloroacetate efficacy and pharmacogenetics in Multiple Myeloma patients in partial remission Anneke C. Blackburn, Dan Dan Tian, Sam Bennett, Lucy A. Coupland, Kathryn Forwood, Yadanar Lwin, Teresa Neeman, Illa Tea, Philip Crispin, and James D’Rozario Presented at 2nd Australian Cancer and Metabolism Meeting, Melbourne 2017.