Lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide via induction of oxidative stress in Leishmania (L.) infantum

Author(s)

Mesquita, Juliana Tonini ^[1] ; Pinto, Erika Gracielle ^{[1, 2]} ; Taniwaki, Noemi Nosomi ^[1] ; Galisteo, Jr., Andres Jimenez ^[2] ; Tempone, Andre Gustavo ^[1]

Affiliation

^[1] Adolfo Lutz Inst, Dept Parasitol, BR-01246900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Med Trop, Lab Protozool, BR-05403000 Sao Paulo - Brazil

• Document type: Journal article
• Source: Acta Tropica; v. 128, n. 3, p. 666-673, DEC 2013.
• Web of Science Citations: 11

Abstract

Studying the cellular death pathways in Leishmania is an important aspect of discovering new antileishmanials. While using a drug repositioning approach, the lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide (NTZ) was investigated against Leishmania (L.) infantum. The in vitro antileishmanial activity and cytotoxicity were assessed using both parasite stages and mammalian NCTC cells, respectively. The lethal action of NTZ was investigated by detecting the phosphatidylserine (PS) exposure, reactive oxygen species (ROS) regulation, plasma membrane permeability, mitochondrial membrane potential and ultrastructural modifications by transmission electron microscopy. NTZ's activity against L. infantum was confirmed, producing IC50 values of 42.71 mu g/mL against promastigotes and 6.78 mu g/mL against intracellular amastigotes. NTZ rapidly altered the cellular metabolism of promastigotes by depolarising the mitochondrial membrane and up-regulating the reactive oxygen species (ROS). In addition, the flow cytometry data revealed an intense and time-dependent exposure of PS in promastigotes. When using SYTOX (R) Green as a fluorescent probe, NTZ demonstrated no interference in plasma membrane permeability. The ultrastructural alterations in promastigotes were time-dependent and caused chromatin condensation, plasma membrane blebbing and mitochondrial swelling. These data suggest that NTZ induced oxidative stress in L. (L.) infantum and might be a useful compound for investigating new therapeutic targets. (C) 2013 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 12/18756-1 - Evaluation of novel alternative therapies with synthetic drugs using in vitro and experimental models of Leishmania (L.) infantum chagasi
• Grantee: André Gustavo Tempone Cardoso
• Support type: Regular Research Grants