Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells

PLoS One. 2017 Jun 23;12(6):e0180061. doi: 10.1371/journal.pone.0180061. eCollection 2017.

Abstract

The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin's reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM-M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antineoplastic Agents / toxicity*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dichloroacetic Acid / toxicity*
  • Electron Transport Complex I / antagonists & inhibitors*
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Metformin / pharmacology
  • Mice
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Rotenone / pharmacology
  • Superoxides / metabolism

Substances

  • Antineoplastic Agents
  • Rotenone
  • Superoxides
  • Metformin
  • Dichloroacetic Acid
  • AMP-Activated Protein Kinases
  • Electron Transport Complex I

Grant support

This study was funded through a charitable donation from Scivation, Inc. to DPD; however, they had no role in the design of the study, collection, analysis and interpretation of the data, or writing of this manuscript.