title: Targeting succinate:ubiquinone reductase potentiates the efficacy of anticancer therapy.
abstract: Mitochondria play a pivotal role in apoptosis: permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic proteins from the intermembrane space of mitochondria are regarded as the key event in apoptosis induction. Here we demonstrate how non-toxic doses of the mitochondrial Complex II inhibitor thenoyltrifluoroacetone (TTFA), which specifically inhibits the ubiquinone-binding site of succinate dehydrogenase (SDH), synergistically stimulated cell death, induced by harmless doses of cisplatin in a panel of chemoresistant neuroblastoma cell lines. Apoptotic cell death was confirmed by cytochrome c release from the mitochondria, cleavage of poly ADP-ribose polymerase, processing of caspase-3, which is an important executive enzyme in apoptosis, and caspase-3-like activity. Methyl malonate, an inhibitor of the SDHA subunit partially reversed apoptosis stimulated by TTFA in SK-N-BE(2) neuroblastoma cells (NB), indicating that sensitization requires oxidation of succinate. In contrast, in IMR-32 NB cells, the same concentrations of TTFA markedly suppressed cisplatin-induced apoptosis. Comparison of oxygen consumption in cisplatin-resistant SK-N-BE(2) and cisplatin-sensitive IMR-32 cells clearly demonstrated impaired Complex II activity in IMR-32 cells. We also found that in SK-N-BE(2) cells co-treatment with cisplatin and TTFA markedly stimulated formation of reactive oxygen species (ROS), whereas in IMR cells, cisplatin-mediated ROS production was attenuated by TTFA, which explains apoptosis suppression in these cells. Thus, functionally active SDH is a prerequisite for the ROS-mediated sensitization to treatment by TTFA.
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Kruspig
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden.
authors.forename: Kadri
authors.initials: K
authors.lastname: Valter
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden; Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Královopolská 135, 612 65 Brno, Czech Republic; Department of Animal Physiology and Immunology, Institute of Experimental Biology, Faculty of Science, Masaryk University, Terezy Novákové 64, 621 00 Brno, Czech Republic.
authors.forename: Belma
authors.initials: B
authors.lastname: Skender
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm, SE-171 77, Sweden; MV Lomonosov Moscow State University, 119991 Moscow, Russia. Electronic address: Vladimir.Gogvadze@ki.se.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009447:Neuroblastoma / Q000473:pathology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D013481:Superoxides; D013804:Thenoyltrifluoroacetone; D019802:Succinic Acid; D042963:Electron Transport Complex II; D002945:Cisplatin
keywords: Apoptosis; Cancer; Mitochondria; Neuroblastoma; Reactive oxygen species; Respiratory chain