title: 3-Bromopyruvic Acid Inhibits Tricarboxylic Acid Cycle and Glutaminolysis in HepG2 Cells.
abstract: OBJECTIVE
  3-bromopyruvate (3BrPA) is an antitumor agent able to inhibit aerobic glycolysis and oxidative phosphorylation, therefore inducing cell death. However, cancer cells are also highly dependent of glutaminolysis and tricarboxylic acid cycle (TCA) regarding survival and 3BrPA action in these metabolic routes is poorly understood.
  
  
  METHODS
  The effect of 3BrPA was characterized in mice liver and kidney mitochondria, as well as in human HepG2 cells.
  
  
  RESULTS
  Low concentration of 3-BrPA significantly affected both glutaminolysis and TCA cycle functions, through inhibition of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and succinate dehydrogenase. Additionally, 3-BrPA treatment significantly decreased the reduced status of thiol groups in HepG2 cells without proportional increase of oxidizing groups, suggesting that these chemical groups are the target of alkylation reactions induced by 3-BrPA.
  
  
  CONCLUSIONS
  This work demonstrates, for the first time, the effect of 3-BrPA in glutaminolysis and TCA cycle. Our results suggest that the combined action of 3-BrPA in glutaminolysis, TCA and glycolysis, inhibiting steps downstream of the glucose and glutamine metabolism, has an antitumor effect.
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil douglas.messeder@gmail.com.
authors.forename: Douglas
authors.initials: D
authors.lastname: Jardim-Messeder
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Moreira-Pacheco
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects*; D005973:Glutamine / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors; D007656:Ketoglutaric Acids / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates / Q000494:pharmacology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D007656:Ketoglutaric Acids; D011773:Pyruvates; D013438:Sulfhydryl Compounds; D005973:Glutamine; C017092:bromopyruvate; D007521:Isocitrate Dehydrogenase; D013385:Succinate Dehydrogenase
keywords: 3-Bromopyruvate; HepG2 cells; TCA cycle; glutaminolysis; liver mitochondria