title: The 8-aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase.
abstract: The 8-aminoquinoline analogue sitamaquine (SQ) is an oral antileishmanial drug currently undergoing phase 2b clinical trials for the treatment of visceral leishmaniasis. In the present study, we investigated the mechanism of action of this drug in Leishmania donovani promastigotes. SQ causes a dose-dependent inhibition of complex II (succinate dehydrogenase) of the respiratory chain in digitonin-permeabilized promastigotes, together with a drop in intracellular ATP levels and a decrease of the mitochondrial electrochemical potential. This is associated with increases of reactive oxygen species and intracellular Ca(2+) levels, a higher percentage of the population with sub-G(1) DNA content, and exposure of phosphatidylserine. Taken together, these results support a lethal mechanism for SQ that involves inhibition of the respiratory chain complex II, which in turn triggers oxidative stress and finally leads to an apoptosis-like death of Leishmania parasites.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, CSIC (IPBLN-CSIC), Parque Tecnológico de Ciencias de la Salud, Avd. del Conocimiento s/n, 18100 Armilla, Granada, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Carvalho
authors.forename: Juan Román
authors.initials: JR
authors.lastname: Luque-Ortega
authors.forename: Carmen
authors.initials: C
authors.lastname: López-Martín
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D042963:Electron Transport Complex II / Q000187:drug effects* / Q000378:metabolism*; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology*
chemical_list: D000634:Aminoquinolines; D017382:Reactive Oxygen Species; D014344:Trypanocidal Agents; D042963:Electron Transport Complex II; C080436:8-aminoquinoline