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JAC Advance Access published online on March 24, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki087
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received November 12, 2004
Revised February 4, 2005
Accepted February 7, 2005

Brief report

Anti-proliferative synergy of lysophospholipid analogues and ketoconazole against Trypanosoma cruzi (Kinetoplastida: Trypanosomatidae): cellular and ultrastructural analysis

Ricardo M. Santa-Rita 1, Renee Lira 2, Helene Santos Barbosa 1, Julio A. Urbina 2, and Solange L. de Castro 1*

1 Departmento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, CP 926, 21045-900, Rio de Janeiro, Brazil
2 Laboratorio de Química Biológica, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Apartado Postal 21.627, Caracas 1020A, Venezuela

* To whom correspondence should be addressed.
Solange L. de Castro, E-mail: solange{at}ioc.fiocruz.br


  Abstract

Objectives: Investigation of the antiproliferative synergy of the lysophospholipid analogues (LPAs) edelfosine, ilmofosine and miltefosine with the ergosterol biosynthesis inhibitor ketoconazole against Trypanosoma cruzi.

Methods: The effect of LPAs, ketoconazole and their combination was evaluated against epimastigotes and intracellular amastigotes by the parameter IC50 leading to construction of isobolograms, for determination of a synergic effect. For epimastigotes, ultrastructural damage induced by these treatments was evaluated by transmission and scanning electron microscopy.

Results: Synergy was confirmed against both epimastigotes and amastigotes of the parasite. Edelfosine or ketoconazole alone induced morphological alterations in the plasma membrane and reservosomes of the parasites, while in combination, they also led to severe mitochondrial damage, formation of autophagic structures and multinucleation. Scanning electron microscopy confirmed the effect at the plasma membrane and also revealed alterations in the shape of the parasites.

Conclusions: Our results describe the synergic anti-proliferative effect of LPAs and ketoconazole against epimastigotes and intracellular amastigotes and suggest that in epimastigotes, plasma membrane, reservosomes and mitochondria are targets of these drugs, possibly by interference with lipid metabolism.

Keywords: T. cruzi; chemotherapy; edelfosine; ilmofosine; miltefosine; synergy.
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