title: Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi.
abstract: l-Buthionine (S,R)-sulfoximine (BSO) increased the toxicity of nifurtimox and benznidazole toward the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi. BSO at 500 muM decreased total glutathione-derived thiols by 70 to 80% in 48 h. In epimastigotes, 500 muM BSO decreased the concentration of nifurtimox needed to inhibit constant growth of the parasites by 50%, from 14.0 to 9.0 muM, and decreased that of benznidazole from 43.6 to 24.1 muM. The survival of epimastigotes or trypomastigotes treated with nifurtimox or benznidazole, as measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) reduction, was significantly decreased by 500 muM BSO. In Vero cells infected with amastigotes, 25 muM BSO was able to potentiate the effect of nifurtimox and benznidazole as measured by the percentage of infected Vero cells multiplied by the average number of intracellular amastigotes (endocytic index). At 0.5 muM nifurtimox, the proportion of Vero cells infected decreased from 27 to 20% and the endocytic index decreased from 2,500 to 980 when 25 muM BSO was added. Similar results were obtained with benznidazole- and BSO-benznidazole-treated cells. This study indicates that potentiation of nifurtimox or benznidazole by BSO could decrease the clinical dose of both drugs and diminish the side effects or the length of therapy.
authors.affiliation: University of Chile, Faculty of Medicine, Molecular and Clinical Pharmacology Program, P.O. Box 70000, Santiago 7, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Faundez
authors.forename: Laura
authors.initials: L
authors.lastname: Pino
authors.forename: Paula
authors.initials: P
authors.lastname: Letelier
authors.forename: Carla
authors.initials: C
authors.lastname: Ortiz
authors.forename: Rodrigo
authors.initials: R
authors.lastname: López
authors.forename: Claudia
authors.initials: C
authors.lastname: Seguel
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
authors.forename: Mario
authors.initials: M
authors.lastname: Pavani
authors.forename: Antonio
authors.initials: A
authors.lastname: Morello
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D009547:Nifurtimox / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests / Q000379:methods; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development; D014709:Vero Cells
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D019328:Buthionine Sulfoximine; D009547:Nifurtimox; C009999:benzonidazole