title: Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
abstract: The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.
authors.affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.
authors.forename: Lili
authors.initials: L
authors.lastname: Guo
authors.affiliation: Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shestov
authors.affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Worth
authors.affiliation: Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: Kavindra
authors.initials: K
authors.lastname: Nath
authors.affiliation: Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and.
authors.forename: David S
authors.initials: DS
authors.lastname: Nelson
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Leeper
authors.affiliation: Laboratory of Molecular Imaging Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 and glickson@mail.med.upenn.edu.
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Glickson
authors.affiliation: From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and ianblair@mail.med.upenn.edu.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008293:Malates / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D064688:Metabolic Flux Analysis; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D009249:NADP / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism
chemical_list: C575376:4,4,4 trifluoro-1-(2-naphthyl)1,3-butanedione; D000970:Antineoplastic Agents; D005650:Fumarates; D007191:Indazoles; D008293:Malates; D009281:Naphthalenes; D017382:Reactive Oxygen Species; C478189:respiratory complex II; D005973:Glutamine; D009249:NADP; C030298:malic acid; D019802:Succinic Acid; D042963:Electron Transport Complex II; D005978:Glutathione; D003931:Diacetyl; C016371:lonidamine
keywords: anticancer drug; cancer therapy; chromatography; drug action; glucose metabolism; glutamate; glutamine; glycolysis; high-performance liquid chromatography (HPLC); mass spectrometry (MS)