1. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate.
- Author
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Sica V, Bravo-San Pedro JM, Izzo V, Pol J, Pierredon S, Enot D, Durand S, Bossut N, Chery A, Souquere S, Pierron G, Vartholomaiou E, Zamzami N, Soussi T, Sauvat A, Mondragón L, Kepp O, Galluzzi L, Martinou JC, Hess-Stumpp H, Ziegelbauer K, Kroemer G, and Maiuri MC
- Subjects
- Animals, Apoptosis Inducing Factor metabolism, Cell Line, Tumor, Electron Transport Complex I metabolism, Female, Glycolysis drug effects, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Mice, Mice, Nude, Mitochondria metabolism, Oxadiazoles pharmacology, Oxidative Phosphorylation drug effects, Poly (ADP-Ribose) Polymerase-1 metabolism, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Proto-Oncogene Proteins c-mdm2 metabolism, Pyrazoles pharmacology, RNA Interference, RNA, Small Interfering metabolism, Tumor Suppressor Protein p53 metabolism, Apoptosis drug effects, Electron Transport Complex I antagonists & inhibitors, Ketoglutaric Acids pharmacology
- Abstract
Inhibition of oxidative phosphorylation (OXPHOS) by 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 (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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