Sica, ValentinaBravo San Pedro, José ManuelMaiuri, Maria Chiara2025-12-152025-12-152019-04Sica 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, Maiuri MC. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate. Cell Reports. 2019 Apr 16;27(3):820–834.2211-124710.1016/j.celrep.2019.03.058https://hdl.handle.net/20.500.14352/128992Inhibition 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal articlehttps://doi.org/10.1016/j.celrep.2019.03.05830995479https://www.sciencedirect.com/science/article/pii/S2211124719303882?via%3Dihubhttps://pubmed.ncbi.nlm.nih.gov/30995479/open access616-006.04MDM2Krebs cycleGlycolysisMitochondrial fragmentationRegulated cell deathParthanatosCancer metabolismCiencias BiomédicasOncología32 Ciencias Médicas3201.01 Oncología