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Antimicrobial Agents and Chemotherapy, March 2004, p. 852-859, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.852-859.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes

Caroline Paris,1 Philippe M. Loiseau,1* Christian Bories,1 and Jaqueline Bréard2*

UMR 8076 CNRS, Chimiothérapie Antiparasitaire,1 INSERM U461, Récepteurs et Signalisation des Interleukines, Faculté de Pharmacie Paris-Sud, 92290 ChÂtenay-Malabry, France2

Received 21 July 2003/ Returned for modification 24 October 2003/ Accepted 31 October 2003

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.

* Corresponding author. Mailing address for Philippe M. Loiseau: UMR 8076 CNRS, Faculté de Pharmacie Paris-Sud, 5 rue Jean-Baptiste Clément, 92290 ChÂtenay-Malabry, France. Phone: (33) 1 46 83 55 53. Fax: (33) 1 46 83 55 57. E-mail: philippe.loiseau{at}cep.u-psud.fr. Mailing address for Jacqueline Bréard: INSERM U461, Faculté de Pharmacie Paris-Sud, 5 rue Jean-Baptiste Clément, 92290 ChÂtenay-Malabry, France. Phone: (33) 1 46 83 57 81. Fax: (33) 1 46 83 54 96. E-mail: jacqueline.breard{at}cep.u-psud.fr.

Antimicrobial Agents and Chemotherapy, March 2004, p. 852-859, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.852-859.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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