title: The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction.
abstract: Despite ongoing efforts, the current treatment for Chagas disease is still unsatisfactory, mainly because of the severe side effects and variable efficacy of the available nitroheterocycles. Our group has been assaying natural quinones isolated from Brazilian flora, and their derivatives, as alternative chemotherapeutic agents against Trypanosoma cruzi. From C-allyl lawsone three naphthofuranquinones were synthesized, which were active against trypomastigotes and epimastigotes. Here, we further investigated the activity and the mechanisms of action of these quinones. They exhibited powerful effects on intracellular amastigotes, presenting low toxicity to the host cells. Ultrastructural analyses of treated epimastigotes and trypomastigotes indicated a potent effect of the three naphthofuranquinones on the parasite mitochondrion, which appeared drastically swollen and with a washed-out matrix profile. Fluorescence-activated cell sorting analysis of rhodamine 123-stained T. cruzi showed that the three naphthofuranquinones caused a potent dose-dependent collapse of the mitochondrial membrane potential, especially in the epimastigote form. Naphthofuranquinones also decreased specifically mitochondrial complex I-III activity in both epimastigotes and trypomastigotes, parallel to a reduction in succinate-induced oxygen consumption. Mitochondrial hydrogen peroxide formation was also increased in epimastigotes after treatment with the naphthofuranquinones. Our results indicate that the trypanocidal action of the naphthofuranquinones is associated with mitochondrial dysfunction, leading to increased reactive oxygen species generation and parasite death.
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-900, Brazil.
authors.forename: Rubem F S
authors.initials: RF
authors.lastname: Menna-Barreto
authors.forename: Renata L S
authors.initials: RL
authors.lastname: Goncalves
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Costa
authors.forename: Raphael S F
authors.initials: RS
authors.lastname: Silva
authors.forename: Antonio V
authors.initials: AV
authors.lastname: Pinto
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Oliveira
authors.forename: Solange L
authors.initials: SL
authors.lastname: de Castro
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004579:Electron Transport / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D008018:Life Cycle Stages / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D009285:Naphthoquinones; D014344:Trypanocidal Agents; D006861:Hydrogen Peroxide