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

GARAVAGLIA, PATRICIA ANDREA; RUBIO, MARÍA FERNANDA; LAVERRIÈRE, MARC; TASSO, LAURA MÓNICA; FICHERA, LAURA EDITH; CANNATA, JOAQUÍN J B; GARCÍA, GABRIELA ANDREA

PARASITOLOGY

CAMBRIDGE UNIV PRESS

Año: 2018 p. 1 - 9

0031-1820

Several ortho-naphthoquinones (o-NQs) have trypanocidal activity against Trypanosomacruzi, the aetiological agent of Chagas disease. Previously, we demonstrated that the aldoketoreductase 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 thanin Nicaragua. Here, we studied the trypanocidal effect and induction of several death phenotypesby β-Lap and 9,10-PQ in epimastigotes of these two strains. The CL Brener strain wasmore resistant to both o-NQs than Nicaragua, indicating that greater TcAKR activity isunlikely to be a major influence on o-NQ toxicity. Evaluation of changes in ROS production,mitochondrial membrane potential, phosphatidylserine exposure and monodansylcadaverinelabelling evidenced that β-Lap and 9,10-PQ induce different death phenotypes depending onthe combination of drug and T. cruzi strain analysed. To study whether TcAKR participates ino-NQ activation in intact parasites, β-Lap and 9,10-PQ trypanocidal effect was next evaluatedin TcAKR-overexpressing parasites. Only β-Lap was more effective and induced greater ROSproduction in TcAKR-overexpressing epimastigotes than in controls, suggesting that TcAKRmay participate in β-Lap activation.