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A novel triazolic naphthofuranquinone induces autophagy in reservosomes and impairment of mitosis in Trypanosoma cruzi

Published online by Cambridge University Press:  23 September 2011

M. C. FERNANDES ,
E. N. DA SILVA JR. ,
A. V. PINTO ,
S. L. DE CASTRO  and
R. F. S. MENNA-BARRETO
M. C. FERNANDES
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-360, Brazil
E. N. DA SILVA JR.
Affiliation:
Instituto de Ciências Exatas, Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
A. V. PINTO
Affiliation:
Núcleo de Pesquisas em Produtos Naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944–970, Brazil
S. L. DE CASTRO
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-360, Brazil
R. F. S. MENNA-BARRETO*
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-360, Brazil
*
*Corresponding author: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040–360, Brazil. Fax: 00 55 21 2562 1432. E-mail: rubemb@ioc.fiocruz.br
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Summary

Chagas' disease, caused by the protozoan Trypanosoma cruzi, represents a serious health problem in Latin America, and the available chemotherapy, which is based on 2 nitro-derivatives, is not satisfactory. In folk medicine, natural products including naphthoquinones have been employed for the treatment of different parasitic diseases. In the pursuit of alternative drugs for Chagas' disease, we investigated the mechanism of action of the triazolic naphthoquinone (TN; 2,2-dimethyl-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-2,3-dihydronaphtho[1,2-b]furan-4,5-dione), which is the most active compound against T. cruzi trypomastigotes among a series of naphthofuranquinones. TN was active against the 3 parasite forms producing a dose-dependent inhibitory effect. In epimastigotes, TN induced reservosome disruption, flagellar blebbing, Golgi disorganization, the presence of cytosolic concentric membrane structures and abnormal multiflagellar parasites. The treatment also led to the appearance of well-developed endoplasmic reticulum profiles surrounding organelles that associated with an increase in monodansylcadaverine labelling, suggesting autophagy as part of the TN mechanism of action. Interestingly, no ultrastructural damage was detected in the mitochondria of naphthoquinone-treated epimastigotes. Flow cytometric analysis demonstrated an impairment of mitosis, an increase in ROS production and the maintenance of mitochondrial membrane potential. TN could be a good starting point in the investigation of a chemotherapeutic approach for the treatment of Chagas' disease.

Keywords

Trypanosoma cruzichemotherapynaphthoquinonesautophagymitosisreactive oxygen species
Type
Research Article
Information
Parasitology , Volume 139 , Issue 1 , January 2012 , pp. 26 - 36
Copyright
Copyright © Cambridge University Press 2011

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