Journal Article

Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against <i>Leishmania amazonensis</i>

Ricardo M. Santa-Rita, Andréa Henriques-Pons, Helene S. Barbosa and Solange L. de Castro

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 54, issue 4, pages 704-710
Published in print October 2004 | ISSN: 0305-7453
Published online October 2004 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh380
Effect of the lysophospholipid analogues edelfosine, ilmofosine and miltefosine against Leishmania amazonensis

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Objectives: Analysis of the effect of edelfosine, ilmofosine and miltefosine on Leishmania amazonensis and of potential targets of these lysophospholipid analogues.

Methods: Quantification and ultrastructural analysis of the effect of lysophospholipid analogues on promastigote forms and on infected peritoneal macrophages, and flow cytometry analysis of treated promastigotes labelled with propidium iodide and rhodamine 123 (Rh123).

Results: The lysophospholipid analogues presented potent antiproliferative activity with IC50/3 days of 1.9–3.4 μM for promastigotes and 4.2–9.0 μM for intracellular amastigotes. Treatment with these analogues in Schneider medium for 1 day led to a dose-dependent decrease in Rh123 fluorescence, an effect more accentuated in edelfosine-treated parasites, suggesting interference with the potential of the mitochondrial membrane. In both forms of L. amazonensis, edelfosine induced extensive mitochondrial damage, multinucleation and, in promastigotes, also led to plasma membrane alterations, formation of autophagic structures and membranous arrangements inside the flagellar pocket.

Conclusions: The alkylglycerophosphocholines edelfosine and ilmofosine were more active than the alkylphosphocholine miltefosine against promastigotes and intracellular amastigotes of L. amazonensis, and ultrastructural and flow cytometry data indicate the mitochondrion as a target of edelfosine.

Keywords: L. amazonensis; alkylglycerophosphocholines; flow cytometry; chemotherapy; electron microscopy

Journal Article.  3112 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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