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A3K2A3-induced apoptotic cell death of Leishmania amazonensis occurs through caspase- and ATP-dependent mitochondrial dysfunction

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Abstract

Leishmaniasis is a neglected tropical disease that affects millions of people worldwide. Current therapies mainly rely on antimonial drugs that are inadequate because of their high toxicity and increased drug resistance. An urgent need exists to discover new, more effective, more affordable, and more target-specific drugs. Pathways that are associated with apoptosis-like cell death have been identified in unicellular eukaryotes, including protozoan parasites. In the present study, we studied the mechanism of cell death that is induced by A3K2A3 against L. amazonensis. A3K2A3 is a dibenzylideneacetone that has an acyclic dienone that is attached to aryl groups in both β-positions, which is similar to curcuminoids and chalcone structures. This compound was previously shown to be safe with regard to cytotoxicity and active against the parasite. Biochemical and morphological approaches were used in the present study. The results suggested that A3K2A3 caused mitochondrial dysfunction in L. amazonensis promastigotes, leading to mechanisms of cell death that share some common phenotypic features with metazoan apoptosis, such as an increase in reactive oxygen species production, a decrease in the adenosine triphosphate ratio, phosphatidylserine exposure, a decrease in cell volume, caspase production, and DNA fragmentation. Altogether, these findings indicate that apoptosis can indeed be triggered by chemotherapeutic agents.

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Acknowledgments

This work was supported through grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq, Capacitação de Aperfeiçoamento de Pessoal de Nível Superior—CAPES, Financiadora de Estudos e Projetos—FINEP, Programa de Pós-Graduação em Ciências Biológicas da Universidade Estadual de Maringá and Complexo de Centrais de Apoio a Pesquisa COMCAP—UEM.

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  1. Programa de Pós-graduação em Ciências Biológicas, Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Bloco B-08, Av. Colombo 5790, Maringá, PR, CEP 87020-900, Brazil

    Francielle Pelegrin Garcia, Jean Henrique da Silva Rodrigues, Tânia Ueda-Nakamura & Celso Vataru Nakamura

  2. LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, CP 676, São Carlos, SP, 13.565-905, Brazil

    Zia Ud Din & Edson Rodrigues-Filho

  3. CERMAV, CNRS, Université Grenoble Alpes, 38000, Grenoble, France

    Rachel Auzély-Velty

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  1. Francielle Pelegrin Garcia
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Correspondence to Celso Vataru Nakamura.

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All of the animal procedures were performed in accordance with guidelines established by the Universidade Estadual de Maringá ethical committee (Protocol No. 029/2014).

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Garcia, F.P., Henrique da Silva Rodrigues, J., Din, Z.U. et al. A3K2A3-induced apoptotic cell death of Leishmania amazonensis occurs through caspase- and ATP-dependent mitochondrial dysfunction. Apoptosis 22, 57–71 (2017). https://doi.org/10.1007/s10495-016-1308-4

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