A strategy for poisoning cancer cell metabolism: Inhibition of oxidative phosphorylation coupled to anaplerotic saturation

Int Rev Cell Mol Biol. 2019:347:27-37. doi: 10.1016/bs.ircmb.2019.07.002. Epub 2019 Jul 29.

Abstract

The combination of inhibitor of oxidative phosphorylation (OXPHOS) with dimethyl-α-ketoglutarate, a cell-permeable precursor of α-ketoglutarate, is highly efficient in killing human cancer cells in vitro or in vivo, in xenotransplanted mice. This effect involves excessive anaplerosis, as demonstrated by the fact that inhibition of isocitrate dehydrogenase-1, IDH1, reduced the efficacy of cancer cell killing by the combination treatment. However, the signal transduction pathway leading to cell death turned out to be complex because it involved numerous atypical cell death effectors (such as AIF, APEX, MDM2, PARP1), as well as a profound remodeling of the transcriptome resulting in reduced expression of glycolytic enzymes. The combined inhibition of OXPHOS and glycolytic ATP generation culminated in a lethal bioenergetic catastrophe.

Keywords: Anaplerosis; Cancer; Cell death; Metabolism; Mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / metabolism
  • Autophagy / drug effects
  • Autophagy / physiology
  • Carcinogenesis* / drug effects
  • Carcinogenesis* / metabolism
  • Drug Delivery Systems
  • Drug Synergism
  • Energy Metabolism / drug effects
  • Humans
  • Ketoglutaric Acids* / administration & dosage
  • Ketoglutaric Acids* / metabolism
  • Mice
  • Neoplasms* / drug therapy
  • Neoplasms* / metabolism
  • Oxadiazoles* / administration & dosage
  • Oxadiazoles* / metabolism
  • Oxidative Phosphorylation / drug effects*
  • Pyrazoles* / administration & dosage
  • Pyrazoles* / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects

Substances

  • 1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine
  • Antineoplastic Agents
  • Ketoglutaric Acids
  • Oxadiazoles
  • Pyrazoles
  • dimethyl alpha-ketoglutarate