Cargando…

DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis

BACKGROUND: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. METHODOLOGY/PRIN...

Descripción completa

Detalles Bibliográficos
Autores principales: Khouri, Ricardo, Novais, Fernanda, Santana, Gisélia, de Oliveira, Camila Indiani, Vannier dos Santos, Marcos André, Barral, Aldina, Barral-Netto, Manoel, Van Weyenbergh, Johan
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006171/
https://www.ncbi.nlm.nih.gov/pubmed/21200432
http://dx.doi.org/10.1371/journal.pone.0014394
_version_ 1782194167518068736
author Khouri, Ricardo
Novais, Fernanda
Santana, Gisélia
de Oliveira, Camila Indiani
Vannier dos Santos, Marcos André
Barral, Aldina
Barral-Netto, Manoel
Van Weyenbergh, Johan
author_facet Khouri, Ricardo
Novais, Fernanda
Santana, Gisélia
de Oliveira, Camila Indiani
Vannier dos Santos, Marcos André
Barral, Aldina
Barral-Netto, Manoel
Van Weyenbergh, Johan
author_sort Khouri, Ricardo
collection PubMed
description BACKGROUND: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p<0.001) and is able to “sterilize” Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p<0.001) and parasite destruction (p<0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p<0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden. CONCLUSIONS/SIGNIFICANCE: Due to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection.
format Text
id pubmed-3006171
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-30061712011-01-03 DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis Khouri, Ricardo Novais, Fernanda Santana, Gisélia de Oliveira, Camila Indiani Vannier dos Santos, Marcos André Barral, Aldina Barral-Netto, Manoel Van Weyenbergh, Johan PLoS One Research Article BACKGROUND: Chemotherapy remains the primary tool for treatment and control of human leishmaniasis. However, currently available drugs present serious problems regarding side-effects, variable efficacy, and cost. Affordable and less toxic drugs are urgently needed for leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate, by microscopy and viability assays, that superoxide dismutase inhibitor diethyldithiocarbamate (DETC) dose-dependently induces parasite killing (p<0.001) and is able to “sterilize” Leishmania amazonensis infection at 2 mM in human macrophages in vitro. We also show that DETC-induced superoxide production (p<0.001) and parasite destruction (p<0.05) were reverted by the addition of the antioxidant N-acetylcysteine, indicating that DETC-induced killing occurs through oxidative damage. Furthermore, ultrastructural analysis by electron microscopy demonstrates a rapid and highly selective destruction of amastigotes in the phagosome upon DETC treatment, without any apparent damage to the host cell, including its mitochondria. In addition, DETC significantly induced parasite killing in Leishmania promastigotes in axenic culture. In murine macrophages infected with Leishmania braziliensis, DETC significantly induced in vitro superoxide production (p = 0.0049) and parasite killing (p = 0.0043). In vivo treatment with DETC in BALB/C mice infected with Leishmania braziliensis caused a significant decrease in lesion size (p<0.0001), paralleled by a 100-fold decrease (p = 0.0087) in parasite burden. CONCLUSIONS/SIGNIFICANCE: Due to its strong leishmanicidal effect in human macrophages in vitro, its in vivo effectiveness in a murine model, and its previously demonstrated in vivo safety profile in HIV treatment, DETC treatment might be considered as a valuable therapeutic option in human leishmaniasis, including HIV/Leishmania co-infection. Public Library of Science 2010-12-21 /pmc/articles/PMC3006171/ /pubmed/21200432 http://dx.doi.org/10.1371/journal.pone.0014394 Text en Khouri et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Khouri, Ricardo
Novais, Fernanda
Santana, Gisélia
de Oliveira, Camila Indiani
Vannier dos Santos, Marcos André
Barral, Aldina
Barral-Netto, Manoel
Van Weyenbergh, Johan
DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title_full DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title_fullStr DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title_full_unstemmed DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title_short DETC Induces Leishmania Parasite Killing in Human In Vitro and Murine In Vivo Models: A Promising Therapeutic Alternative in Leishmaniasis
title_sort detc induces leishmania parasite killing in human in vitro and murine in vivo models: a promising therapeutic alternative in leishmaniasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006171/
https://www.ncbi.nlm.nih.gov/pubmed/21200432
http://dx.doi.org/10.1371/journal.pone.0014394
work_keys_str_mv AT khouriricardo detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT novaisfernanda detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT santanagiselia detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT deoliveiracamilaindiani detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT vannierdossantosmarcosandre detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT barralaldina detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT barralnettomanoel detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis
AT vanweyenberghjohan detcinducesleishmaniaparasitekillinginhumaninvitroandmurineinvivomodelsapromisingtherapeuticalternativeinleishmaniasis