Title: Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine.
Authors: Guo, Lili; Shestov, Alexander A; Worth, Andrew J; Nath, Kavindra; Nelson, David S; Leeper, Dennis B; Glickson, Jerry D; Blair, Ian A
Published In J Biol Chem, (2016 Jan 01)
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.
PubMed ID: 26521302
MeSH Terms: Antineoplastic Agents/pharmacology*; Cell Death/drug effects; Cell Line, Tumor; Citric Acid Cycle/drug effects; Diacetyl/analogs & derivatives; Diacetyl/pharmacology; Electron Transport Complex II/antagonists & inhibitors*; Electron Transport Complex II/metabolism; Fumarates/metabolism; Glutamine/metabolism; Glutathione/metabolism; Humans; Indazoles/pharmacology*; Malates/metabolism; Melanoma/metabolism; Melanoma/pathology; Metabolic Flux Analysis; Mitochondria/drug effects; Mitochondria/metabolism*; Models, Biological; NADP/metabolism; Naphthalenes/pharmacology; Oxidation-Reduction/drug effects; Pentose Phosphate Pathway/drug effects; Reactive Oxygen Species/metabolism; Succinic Acid/metabolism