Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/30820
Title: The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction
Authors: Menna-Barreto, Rubem F. S.
Goncalves, Renata L. S.
Costa, Elaine M.
Silva, Raphael S. F.
Pinto, Antonio V
Oliveira, Marcus F.
Castro, Solange L. de
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Programa de Biologia Molecular e Biotecnologia. Laboratório de Bioquímica Redox. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Núcleo de Pesquisas de Produtos Naturais. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Núcleo de Pesquisas de Produtos Naturais. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Bioquímica Médica. Programa de Biologia Molecular e Biotecnologia. Laboratório de Bioquímica Redox. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.
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.
Keywords: Trypanosoma cruzi
Chagas Disease
Chemotherapy
Naphthoquinones
Reactive oxygen species
Superoxide
Metabolism
Free radicals
keywords: Trypanosoma cruzi
Doença de Chagas
Metabolismo
Radicais livres
Quimioterapia
Naftoquinonas
Superóxido
espécies que reagem ao oxigênio
Issue Date: 2009
Publisher: Elsevier
Citation: MENNA-BARRETO, Rubem F. S. et al. The effects on Trypanosoma cruzi of novel synthetic naphtoquinones are mediated by mytochondrial dysfucntion. Free Radical Biology & Medicine, Free Radical Biology & Medicine, v.47, p.644-653, 2009.
DOI: 10.1016/j.freeradbiomed.2009.06.004
ISSN: 0891-5849
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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