title: 3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system.
abstract: 3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 μM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate-dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment.
authors.affiliation: Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche, Via G. Amendola, 165/A, 70126, Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.affiliation: Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche, Via G. Amendola, 165/A, 70126, Bari, Italy.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Vacca
authors.affiliation: Istituto di Biomembrane e Bioenergetica, Consiglio Nazionale delle Ricerche, Via G. Amendola, 165/A, 70126, Bari, Italy. l.debari@ibbe.cnr.it.
authors.forename: Lidia
authors.initials: L
authors.lastname: de Bari
mesh_terms: D016923:Cell Death; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D011471:Prostatic Neoplasms; D011773:Pyruvates / Q000378:metabolism*
chemical_list: D011773:Pyruvates; C017092:bromopyruvate
keywords: 3-bromopyruvate; Glycolysis; Glyoxalase system; LNCaP cells; Mitochondrial bioenergetics; PC-3 cells