Please use this identifier to cite or link to this item: http://www.arca.fiocruz.br/handle/icict/7730
Title: 17-AAG kills intracellular Leishmania amazonensis while reducing inflammatory responses in infected macrophages.
Authors: Petersen, Antonio Luis de Oliveira Almeida
Guedes, Carlos Eduardo Sampaio
Versoza, Carolina Leite
Lima, José Geraldo Bomfim
Freitas, Luiz Antonio Rodrigues de
Borges, Valeria de Matos
Veras, Patrícia Sampaio Tavares
Affilliation: Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil / Universidade Federal da Bahia. Departamento de Anatomia Patológica e Medicina Legal. Salvador, Bahia, Brazil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil / Universidade Federal da Bahia. Departamento de Anatomia Patológica e Medicina Legal. Salvador, Bahia, Brazil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil / Universidade Federal da Bahia. Departamento de Anatomia Patológica e Medicina Legal. Salvador, Bahia, Brazil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório Integrado de Microbiologia e Imunoregulação. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Laboratório de Patologia e Biointervenção. Salvador, BA, Brasil
Abstract: 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.
DeCS: Benzoquinonas/farmacologia
Inflamação/patologia
Espaço Intracelular/parasitologia
Lactamas Macrocíclicas/farmacologia
Leishmania mexicana/efeitos de drogas
Macrófagos/patologia
Animais
Autofagia/efeitos de drogas
Benzoquinonas/uso terapêutico
Sobrevivência Celular/efeitos de drogas
Citocinas/biossíntese
Feminino
Mediadores da Inflamação/metabolismo
Espaço Intracelular/efeitos de drogas
Lactamas Macrocíclicas/uso terapêutico
Leishmania mexicana/crescimento & desenvolvimento
Leishmaniose/quimioterapia
Macrófagos/efeitos de drogas
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Oxirredução/efeitos de drogas
Oxigênio/metabolismo
Parasitos/crescimento & desenvolvimento
Issue Date: 2012
Publisher: University of California Merced
Citation: PETERSEN, A. L. de O. et al. 17-AAG kills intracellular Leishmania amazonensis while reducing inflammatory responses in infected macrophages. PLoS One, v. 7, n. 11, p. e49496, 2012.
ISSN: 1932-6203
10.1371/journal.pone.0049496
Copyright: open access
Appears in Collections:CPqGM - Artigos de Periódicos

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