Antiproliferative activity of the dibenzylideneacetone derivate (E)-3-ethyl-4-(4-nitrophenyl)but‑3-en-2-one in Trypanosoma cruzi.

Autor: de Paula JC; 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., Bakoshi ABK; 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., Lazarin-Bidóia D; 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., Ud Din Z; LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, CP 676, São Carlos, SP 13.565-905, Brazil., Rodrigues-Filho E; LaBioMMi, Departamento de Química, Universidade Federal de São Carlos, CP 676, São Carlos, SP 13.565-905, Brazil., Ueda-Nakamura T; 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., Nakamura CV; 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. Electronic address: cvnakamura@uem.br.
Jazyk: angličtina
Zdroj: Acta tropica [Acta Trop] 2020 Nov; Vol. 211, pp. 105653. Date of Electronic Publication: 2020 Aug 08.
DOI: 10.1016/j.actatropica.2020.105653
Abstrakt: Chagas disease is one of the most prevalent neglected diseases in the world. The illness is caused by Trypanosoma cruzi, a protozoan parasite with a complex life cycle and three morphologically distinct developmental stages. Nowadays, the only treatment is based on two nitro-derivative drugs, benznidazole and nifurtimox, which cause serious side effects. Since the treatment is limited, the search for new treatment options for patients with Chagas disease is highly necessary. In this study we analyzed the substance A11K3, a dibenzylideneacetone (DBA). DBAs have an acyclic dienone attached to aryl groups in both β-positions and studies have shown that they have biological activity against tumors cells, bacteria, and protozoa such as T. cruzi and Leishmania spp. Here we show that A11K3 is active against all three T. cruzi evolutionary forms: the epimastigote (IC 50  = 3.3 ± 0.8), the trypomastigote (EC 50  = 24 ± 4.3) and the intracellular amastigote (IC 50  = 9.3 ± 0.5 µM). A cytotoxicity assay in LLCMK 2 cells showed a CC 50 of 239.2 ± 15.7 µM giving a selectivity index (CC 50 /IC 50 ) of 72.7 for epimastigotes, 9.9 for trypomastigotes and 25.9 for intracellular amastigotes. Morphological and ultrastructural analysis of the parasites treated with A11K3 by TEM and SEM revealed alterations in the Golgi complex, mitochondria, plasma membrane and cell body, with an increase of autophagic vacuoles and lipid bodies. Biochemical assays of A11K3-treated T. cruzi showed an increase of ROS, plasma membrane ruptures, lipid peroxidation, mitochondrial membrane depolarization with a decrease in ATP and accumulation of autophagic vacuoles. The results lead to the hypothesis that A11K3 causes death of the protozoan through events such as plasma membrane and mitochondrial alterations and autophagy, characteristic of cell collapse.
Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: