Affiliation:
1. UMR 8076 CNRS, Chimiothérapie Antiparasitaire
2. INSERM U461, Récepteurs et Signalisation des Interleukines, Faculté de Pharmacie Paris-Sud, 92290 ChÂtenay-Malabry, France
Abstract
ABSTRACT
Miltefosine (hexadecylphosphocholine [HePC]) has proved to be a potent oral treatment for human visceral leishmaniasis due to
Leishmania donovani
. The molecular mechanisms that contribute to the antileishmanial activity of HePC are still unknown. We report that in wild-type promastigotes of
Leishmania donovani
HePC is able to induce a cell death process with numerous cytoplasmic, nuclear, and membrane features of metazoan apoptosis, including cell shrinkage, DNA fragmentation into oligonucleosome-sized fragments, and phosphatidylserine exposure. None of these changes were detected in an HePC-resistant clone treated with the same drug concentration. Therefore, HePC does not appear to kill
L. donovani
promastigotes by a direct toxic mechanism but, rather, kills the promastigotes by an indirect one. Pretreatment of wild-type promastigotes with two broad caspase inhibitors,
z
-Val-Ala-
dl
-Asp(methoxy)-fluoromethylketone and Boc-Asp(methoxy)-fluoromethylketone, as well as a broad protease inhibitor, calpain inhibitor I, prior to drug exposure interfered with DNA fragmentation but did not prevent cell shrinkage or phosphatidylserine externalization. These data suggest that at least part of the apoptotic machinery operating in wild-type promastigotes involves proteases. Identification of the death-signaling pathways activated in HePC-sensitive parasites appears to be essential for a better understanding of the molecular mechanisms of action and resistance in these parasites.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference69 articles.
1. Ameisen, J. C. 1995. Apoptosis in a unicellular eukaryotes (Trypanosoma cruzi): implications for the evolutionary origin and role of programmed cell in the control of cell proliferation, differentiation and survival. Cell Death Differ. 2:285-300.
2. Ameisen, J. C. 2002. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ.9:367-393.
3. Aravind, L., V. M. Dixit, and E. V. Koonin. 2001. Apoptotic molecular machinery: vastly increased complexity in vertebrates revealed by genome comparisons. Science291:1279-1284.
4. Arnoult, D., K. Akarid, A. Grodet, P. X. Petit, J. Estaquier, and J. C. Ameisen. 2002. On the evolution of programmed cell death: apoptosis of the unicellular eukaryote Leishmania major involves cysteine proteinase activation and mitochondrion permeabilization. Cell Death Differ.9:65-81.
5. Boggs, K., C. O. Rock, and S. Jackowski. 1998. The antiproliferative effect of hexadecylphosphocholine toward HL60 cells is prevented by exogenous lysophosphatidylcholine. Biochim. Biophys. Acta1389:1-12.
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