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Trypanosoma cruzi: death phenotypes induced by ortho-naphthoquinone substrates of the aldo-keto reductase (TcAKR). Role of this enzyme in the mechanism of action of β-lapachone

Published online by Cambridge University Press:  05 February 2018

Patricia Andrea Garavaglia
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
María Fernanda Rubio
Affiliation:
Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari (IDIM-CONICET), Universidad de Buenos Aires, Ciudad de Buenos Aires (1427), Argentina
Marc Laverrière
Affiliation:
Instituto de Investigaciones Biotecnológicas (IIB–INTECH), Universidad Nacional de General San Martín-CONICET, San Martín (1650), Prov. Buenos Aires, Argentina
Laura Mónica Tasso
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
Laura Edith Fichera
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
Joaquín J B Cannata
Affiliation:
Instituto de Investigaciones Biotecnológicas (IIB–INTECH), Universidad Nacional de General San Martín-CONICET, San Martín (1650), Prov. Buenos Aires, Argentina
Gabriela Andrea García*
Affiliation:
Instituto Nacional de Parasitología ‘Dr. Mario Fatala Chaben’-A.N.L.I.S. ‘Dr. Carlos G. Malbrán’, Ciudad de Buenos Aires (1063), Argentina
*
Author for correspondence: Gabriela Andrea García, E-mail: gaandgarcia@yahoo.com

Abstract

Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldo-keto reductase from this parasite (TcAKR) reduces o-NQs, such as β-lapachone (β-Lap) and 9,10-phenanthrenequinone (9,10-PQ), with concomitant reactive oxygen species (ROS) production. Recent characterization of TcAKR activity and expression in two T. cruzi strains, CL Brener and Nicaragua, showed that TcAKR expression is 2.2-fold higher in CL Brener than in Nicaragua. Here, we studied the trypanocidal effect and induction of several death phenotypes by β-Lap and 9,10-PQ in epimastigotes of these two strains. The CL Brener strain was more resistant to both o-NQs than Nicaragua, indicating that greater TcAKR activity is unlikely to be a major influence on o-NQ toxicity. Evaluation of changes in ROS production, mitochondrial membrane potential, phosphatidylserine exposure and monodansylcadaverine labelling evidenced that β-Lap and 9,10-PQ induce different death phenotypes depending on the combination of drug and T. cruzi strain analysed. To study whether TcAKR participates in o-NQ activation in intact parasites, β-Lap and 9,10-PQ trypanocidal effect was next evaluated in TcAKR-overexpressing parasites. Only β-Lap was more effective and induced greater ROS production in TcAKR-overexpressing epimastigotes than in controls, suggesting that TcAKR may participate in β-Lap activation.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2018 

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Trypanosoma cruzi: death phenotypes induced by ortho-naphthoquinone substrates of the aldo-keto reductase (TcAKR). Role of this enzyme in the mechanism of action of β-lapachone
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