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

• Autores: Garavaglia, Patricia A; Rubio, María Fernanda; Laverrière, Marc; Tasso, Laura Mónica; Fichera, Laura E.; Cannata, Joaquín J B; García, Gabriela Andrea
• Año de publicación: 2018
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Parasitology 2018; 145(9):1251-1259.
• Materia: Muerte celular regulada; Enfermedad de Chagas; Quimioterapia
• Institución: Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"

Fil: Garavaglia, Patricia A ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.
Fil: Rubio, María Fernanda. Laboratorio de Biología Molecular y Apoptosis,Instituto de Investigaciones Médicas Alfredo Lanari (IDIM-CONICET),Universidad de Buenos Aires,Ciudad de Buenos Aires (1427); Argentina.
Fil: Laverrière, Marc. Instituto de Investigaciones Biotecnológicas (IIB-INTECH),Universidad Nacional de General San Martín-CONICET,San Martín (1650),Prov. Buenos Aires; Argentina.
Fil: Tasso, Laura Mónica. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.
Fil: Fichera, Laura E. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.
Fil: Cannata, Joaquín J B. Instituto de Investigaciones Biotecnológicas (IIB-INTECH),Universidad Nacional de General San Martín-CONICET,San Martín (1650),Prov. Buenos Aires; Argentina.
Fil: García, Gabriela Andrea. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Parasitología; Argentina.
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.