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 beta-lapachone.
Garavaglia, P. A., Rubio, M. F., Laverriere, M., Tasso, L. M., Fichera, L. E., Cannata, J. J. B. and Garcia, G. A.
Instituto Nacional de Parasitologia 'Dr. Mario Fatala Chaben'-A.N.L.I.S. 'Dr. Carlos G. Malbran',Ciudad de Buenos Aires (1063),Argentina.
Laboratorio de Biologia Molecular y Apoptosis,Instituto de Investigaciones Medicas Alfredo Lanari (IDIM-CONICET),Universidad de Buenos Aires,Ciudad de Buenos Aires (1427),Argentina.
Instituto de Investigaciones Biotecnologicas (IIB-INTECH),Universidad Nacional de General San Martin-CONICET,San Martin (1650),Prov. Buenos Aires,Argentina.
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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 beta-lapachone (beta-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 beta-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 beta-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, beta-Lap and 9,10-PQ trypanocidal effect was next evaluated in TcAKR-overexpressing parasites. Only beta-Lap was more effective and induced greater ROS production in TcAKR-overexpressing epimastigotes than in controls, suggesting that TcAKR may participate in beta-Lap activation.
Parasitology 145(9): 1251-1259 (2018)