Journal
PARASITOLOGY
Volume 141, Issue 6, Pages 814-825Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0031182013001704
Keywords
autophagy; apoptosis; sirtuin inhibitors; KH-TFMDI; Chagas disease
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Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- Financiadora de Estudos e Projetos (FINEP)
- Fundacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
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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 center dot 5 +/- 0 center dot 2 mu m, which is significantly lower than the IC50 of benznidazole. The compound also lysed the highly infectious bloodstream trypomastigotes (BST) with LC50 values of 0 center dot 8 +/- 0 center dot 3 mu m at 4 degrees C and 2 center dot 5 +/- 1 center dot 1 mu m at 37 degrees 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.
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