Antimonial-mediated DNA fragmentation in Leishmania infantum amastigotes

被引:116
作者
Sereno, D
Holzmuller, P
Mangot, I
Cuny, G
Ouaissi, A
Lemesre, JL
机构
[1] Ctr IRD, INSERM, CJF N9604, F-34032 Montpellier 1, France
[2] Ctr IRD, Lab Parasitol & Entomol Mol, F-34032 Montpellier 1, France
[3] Ctr IRD, Lab Biol Parasitaire, F-34032 Montpellier 1, France
关键词
D O I
10.1128/AAC.45.7.2064-2069.2001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The basic treatment of leishmaniasis consists in the administration of pentavalent antimonials. The mechanisms that contribute to pentavalent antimonial toxicity against the intracellular stage of the parasite (i.e., amastigote) are still unknown. In this study, the combined use of several techniques including DNA fragmentation assay and in situ and cytofluorometry terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling methods and YOPRO-1 staining allowed us to demonstrate that potassium antimonyl tartrate, an Sb(III)-containing drug, was able to induce cell death associated with DNA fragmentation in axenic amastigotes of Leishmania infantum at low concentrations (10 mug/ml). This observation was in close correlation with the toxicity of Sb(III) species against axenic amastigotes (50% inhibitory concentration of 4.75 mug/ml). Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase-1, caspase-3, calpain, cysteine protease, or proteasome activation. Altogether, our results demonstrate that the antileishmanial toxicity of Sb(III) antimonials is associated with parasite oligonucleosomal DNA fragmentation, indicative of the occurrence of late events in the overall process of apoptosis. The elucidation of the biochemical pathways leading to cell death could allow the isolation of new therapeutic targets.
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页码:2064 / 2069
页数:6
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