Cargando…
17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages
BACKGROUND: Leishmaniasis is a neglected endemic disease with a broad spectrum of clinical manifestations. Pentavalent antimonials have been the treatment of choice for the past 70 years and, due to the emergence of resistant cases, the efficacy of these drugs has come under scrutiny. Second-line dr...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496716/ https://www.ncbi.nlm.nih.gov/pubmed/23152914 http://dx.doi.org/10.1371/journal.pone.0049496 |
_version_ | 1782249670103269376 |
---|---|
author | Petersen, Antonio Luis de Oliveira Almeida Guedes, Carlos Eduardo Sampaio Versoza, Carolina Leite Lima, José Geraldo Bomfim de Freitas, Luiz Antônio Rodrigues Borges, Valéria Matos Veras, Patrícia Sampaio Tavares |
author_facet | Petersen, Antonio Luis de Oliveira Almeida Guedes, Carlos Eduardo Sampaio Versoza, Carolina Leite Lima, José Geraldo Bomfim de Freitas, Luiz Antônio Rodrigues Borges, Valéria Matos Veras, Patrícia Sampaio Tavares |
author_sort | Petersen, Antonio Luis de Oliveira Almeida |
collection | PubMed |
description | BACKGROUND: Leishmaniasis is a neglected endemic disease with a broad spectrum of clinical manifestations. Pentavalent antimonials have been the treatment of choice for the past 70 years and, due to the emergence of resistant cases, the efficacy of these drugs has come under scrutiny. Second-line drugs are less efficacious, cause a range of side effects and can be costly. The formulation of new generations of drugs, especially in developing countries, has become mandatory. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the anti-leishmanial effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, in vitro. This inhibitor is currently in clinical trials for cancer treatment; however, its effects against intracellular Leishmania remain untested. Macrophages infected with L. amazonensis were treated with 17-AAG (25–500 nM) and parasite load was quantified using optical microscopy. Parasite load declined in 17-AAG-treated macrophages in a dose- and time-dependent manner. Intracellular parasite death became irreversible after 4 h of treatment with 17-AAG, and occurred independent of nitric oxide (NO) and superoxide (O(2) (−)) production. Additionally, intracellular parasite viability was severely reduced after 48 h of treatment. Interestingly, treatment with 17-AAG reduced pro-inflammatory mediator production, including TNF-α, IL-6 and MCP-1, yet IL-12 remained unaffected. Electron microscopy revealed morphological alterations, such as double-membrane vacuoles and myelin figures at 24 and 48 h after 17-AAG treatment. CONCLUSIONS/SIGNIFICANCE: The HSP90 inhibitor, 17-AAG, possesses high potency under low dosage and reduces both pro-inflammatory and oxidative molecule production. Therefore, further studies are warranted to investigate this inhibitor’s potential in the development of new generations of anti-leishmanials. |
format | Online Article Text |
id | pubmed-3496716 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34967162012-11-14 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages Petersen, Antonio Luis de Oliveira Almeida Guedes, Carlos Eduardo Sampaio Versoza, Carolina Leite Lima, José Geraldo Bomfim de Freitas, Luiz Antônio Rodrigues Borges, Valéria Matos Veras, Patrícia Sampaio Tavares PLoS One Research Article BACKGROUND: Leishmaniasis is a neglected endemic disease with a broad spectrum of clinical manifestations. Pentavalent antimonials have been the treatment of choice for the past 70 years and, due to the emergence of resistant cases, the efficacy of these drugs has come under scrutiny. Second-line drugs are less efficacious, cause a range of side effects and can be costly. The formulation of new generations of drugs, especially in developing countries, has become mandatory. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the anti-leishmanial effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, in vitro. This inhibitor is currently in clinical trials for cancer treatment; however, its effects against intracellular Leishmania remain untested. Macrophages infected with L. amazonensis were treated with 17-AAG (25–500 nM) and parasite load was quantified using optical microscopy. Parasite load declined in 17-AAG-treated macrophages in a dose- and time-dependent manner. Intracellular parasite death became irreversible after 4 h of treatment with 17-AAG, and occurred independent of nitric oxide (NO) and superoxide (O(2) (−)) production. Additionally, intracellular parasite viability was severely reduced after 48 h of treatment. Interestingly, treatment with 17-AAG reduced pro-inflammatory mediator production, including TNF-α, IL-6 and MCP-1, yet IL-12 remained unaffected. Electron microscopy revealed morphological alterations, such as double-membrane vacuoles and myelin figures at 24 and 48 h after 17-AAG treatment. CONCLUSIONS/SIGNIFICANCE: The HSP90 inhibitor, 17-AAG, possesses high potency under low dosage and reduces both pro-inflammatory and oxidative molecule production. Therefore, further studies are warranted to investigate this inhibitor’s potential in the development of new generations of anti-leishmanials. Public Library of Science 2012-11-13 /pmc/articles/PMC3496716/ /pubmed/23152914 http://dx.doi.org/10.1371/journal.pone.0049496 Text en © 2012 Petersen 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 Petersen, Antonio Luis de Oliveira Almeida Guedes, Carlos Eduardo Sampaio Versoza, Carolina Leite Lima, José Geraldo Bomfim de Freitas, Luiz Antônio Rodrigues Borges, Valéria Matos Veras, Patrícia Sampaio Tavares 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title | 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title_full | 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title_fullStr | 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title_full_unstemmed | 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title_short | 17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages |
title_sort | 17-aag kills intracellular leishmania amazonensis while reducing inflammatory responses in infected macrophages |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496716/ https://www.ncbi.nlm.nih.gov/pubmed/23152914 http://dx.doi.org/10.1371/journal.pone.0049496 |
work_keys_str_mv | AT petersenantonioluisdeoliveiraalmeida 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT guedescarloseduardosampaio 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT versozacarolinaleite 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT limajosegeraldobomfim 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT defreitasluizantoniorodrigues 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT borgesvaleriamatos 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages AT veraspatriciasampaiotavares 17aagkillsintracellularleishmaniaamazonensiswhilereducinginflammatoryresponsesininfectedmacrophages |