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

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.

• Authors: Valentina Sica, José Manuel Bravo-San Pedro, Guido Kroemer
• Journal: International review of cell and molecular biology (Int Rev Cell Mol Biol) Vol. 347 Pg. 27-37 ( 2019) ISSN: 1937-6448 [Print] Netherlands
• PMID: 31451215 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

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