title: 3-bromopyruvate inhibits glycolysis, depletes cellular glutathione, and compromises the viability of cultured primary rat astrocytes.
abstract: The pyruvate analogue 3-bromopyruvate (3-BP) is an electrophilic alkylator that is considered a promising anticancer drug because it has been shown to kill cancer cells efficiently while having little toxic effect on nontumor cells. To test for potential adverse effects of 3-BP on brain cells, we exposed cultured primary rat astrocytes to 3-BP and investigated the effects of this compound on cell viability, glucose metabolism, and glutathione (GSH) content. The presence of 3-BP severely compromised cell viability and slowed cellular glucose consumption and lactate production in a time- and concentration-dependent manner, with half-maximal effects observed at about 100 µM 3-BP after 4 hr of incubation. The cellular hexokinase activity was not affected in 3-BP-treated astrocytes, whereas within 30 min after application of 3-BP the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was inhibited, and cellular GSH content was depleted in a concentration-dependent manner, with half-maximal effects observed at about 30 µM 3-BP. The depletion of cellular GSH after exposure to 100 µM 3-BP was not prevented by the presence of 10 mM of the monocarboxylates lactate or pyruvate, suggesting that 3-BP is not taken up into astrocytes predominantly by monocarboxylate transporters. The data suggest that inhibition of glycolysis by inactivation of GAPDH and GSH depletion contributes to the toxicity that was observed for 3-BP-treated cultured astrocytes.
authors.affiliation: Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Ehrke
authors.affiliation: Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Arend
authors.affiliation: Center for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, Bremen, Germany.|Center for Environmental Research and Sustainable Technology, University of Bremen, Bremen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dringen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013696:Temperature
chemical_list: D004791:Enzyme Inhibitors; D011773:Pyruvates; D019344:Lactic Acid; C017092:bromopyruvate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006593:Hexokinase; D005978:Glutathione; D005947:Glucose
keywords: 3-bromopyruvate; GAPDH; GSH; glycolysis; toxicity