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Inhibition of NAD+-dependent histone deacetylases (sirtuins) causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi

Published online by Cambridge University Press:  06 February 2014

PHERCYLES VEIGA-SANTOS ,
LISSA CATHERINE REIGNAULT ,
KILIAN HUBER ,
FRANZ BRACHER ,
WANDERLEY DE SOUZA  and
TECIA MARIA ULISSES DE CARVALHO
PHERCYLES VEIGA-SANTOS
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
LISSA CATHERINE REIGNAULT
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
KILIAN HUBER
Affiliation:
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, A-1090 Vienna, Austria
FRANZ BRACHER
Affiliation:
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany
WANDERLEY DE SOUZA
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil Instituto Nacional de Metrologia, Qualidade e Tecnologia – Inmetro, Duque de Caxias, Rio de Janeiro, Brazil
TECIA MARIA ULISSES DE CARVALHO*
Affiliation:
Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Bloco G, Ilha do Fundão, Rio de Janeiro, CEP 21941-902, Brazil Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil
*
*Corresponding author: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Bloco G, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, CEP 21949-900, Brazil. E-mail: tecia@biof.ufrj.br
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Summary

Chagas disease, which is caused by the parasite Trypanosoma cruzi, affects approximately 7–8 million people in Latin America. The drugs available to treat this disease are ineffective against chronic phase disease and are associated with toxic side effects. Therefore, the development of new compounds that can kill T. cruzi at low concentrations is critically important. Herein, we report the effects of a novel 3-arylideneindolin-2-one that inhibits sirtuins, which are highly conserved proteins that are involved in a variety of physiological processes. The compound KH-TFMDI was tested against the epimastigote, trypomastigote and amastigote forms of T. cruzi, and its effects were evaluated using flow cytometry, light and electron microscopy. KH-TFMDI inhibited the replication of T. cruzi intracellular amastigotes with an IC50 of 0·5±0·2 μm, which is significantly lower than the IC50 of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC50 values of 0·8±0·3 μm at 4 °C and 2·5±1·1 μm at 37 °C. KH-TFMDI inhibited cytokinesis and induced several morphological changes in the parasite, leading to its death by apoptosis and autophagy. This study highlights sirtuins as a potential new target for Chagas disease therapy.

Keywords

Chagas diseasesirtuin inhibitorsKH-TFMDIautophagyapoptosis
Type
Research Article
Information
Parasitology , Volume 141 , Issue 6 , May 2014 , pp. 814 - 825
Copyright
Copyright © Cambridge University Press 2014 

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