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PLoS Negl Trop Dis. 2010 Mar 30;4(3):e642. doi: 10.1371/journal.pntd.0000642.

Nelfinavir, an HIV-1 protease inhibitor, induces oxidative stress-mediated, caspase-independent apoptosis in Leishmania amastigotes.

Author information

1
Centre de Recherche en Infectiologie, Centre Hospitalier de l'Université Laval, Université Laval, Québec, Canada.

Abstract

BACKGROUND:

Visceral leishmaniasis has now emerged as an important opportunistic disease in patients coinfected with human immunodeficiency virus type-1 (HIV-1). Although the effectiveness of HIV-1 protease inhibitors, such as nelfinavir, in antiretroviral therapies is well documented, little is known of the impact of these drugs on Leishmania in coinfected individuals.

METHODOLOGY AND PRINCIPAL FINDINGS:

Here, we show that nelfinavir generates oxidative stress in the parasite, leading to altered physiological parameters such as an increase in the sub-G1 DNA content, nuclear DNA fragmentation and loss of mitochondrial potential, which are all characteristics of apoptosis. Pretreatment of axenic amastigotes with the caspase inhibitor z-VAD-fmk did not inhibit the increase in sub-G1 DNA content in nelfinavir-treated parasites, suggesting therefore that this antiviral agent does not kill Leishmania amastigotes in a caspase-dependent manner. Furthermore, we observed that the mitochondrial resident protein endonuclease G is involved. We also demonstrate that parasites overexpressing GSH1 (the rate limiting enzyme of glutathione biosynthesis) were more resistant to nelfinavir when compared to untransfected controls.

CONCLUSIONS AND SIGNIFICANCE:

These data suggest that nelfinavir induces oxidative stress in Leishmania amastigotes, culminating in caspase-independent apoptosis, in which DNA is degraded by endonuclease G. This study provides a rationale for future, long-term design of new therapeutic strategies to test nelfinavir as a potential antileishmanial agent as well as for possible future use in Leishmania/HIV-1 coinfections.

PMID:
20361030
PMCID:
PMC2846936
DOI:
10.1371/journal.pntd.0000642
[Indexed for MEDLINE]
Free PMC Article

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