RT Journal Article
T1 Lethal poisoning of cancer cells by respiratory chain inhibition plus dimethyl α-ketoglutarate
A1 Sica, Valentina
A1 Bravo San Pedro, José Manuel
A1 Maiuri, Maria Chiara
AB 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.
PB Elsevier (Cell Press)
SN 2211-1247
YR 2019
FD 2019-04
LK https://hdl.handle.net/20.500.14352/128992
UL https://hdl.handle.net/20.500.14352/128992
LA eng
NO 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, Maiuri MC. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate. Cell Reports. 2019 Apr 16;27(3):820–834.
DS Docta Complutense
RD 1 ene 2026