Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis.
Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.
Carvalho
Luis
L
Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, Granada, Spain.
Luque-Ortega
Juan Román
JR
Manzano
José Ignacio
JI
Castanys
Santiago
S
Rivas
Luis
L
Gamarro
Francisco
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D014450:Electron Transport Complex III / Q000187:drug effects*; D007891:Leishmania / Q000187:drug effects* / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D000634:Aminoquinolines; D000962:Antimalarials; D017382:Reactive Oxygen Species; C055852:tafenoquine; D000255:Adenosine Triphosphate; D014450:Electron Transport Complex III; D002118:Calcium