Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis.
BACKGROUND: Leishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock P...
Published in: | PLoS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0003275 https://doaj.org/article/c953a2b8329f400782de8297d4e8e508 |
id |
ftdoajarticles:oai:doaj.org/article:c953a2b8329f400782de8297d4e8e508 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:c953a2b8329f400782de8297d4e8e508 2023-05-15T15:09:29+02:00 Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. Diego M Santos Antonio L O A Petersen Fabiana S Celes Valeria M Borges Patricia S T Veras Camila I de Oliveira 2014-10-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003275 https://doaj.org/article/c953a2b8329f400782de8297d4e8e508 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4207694?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003275 https://doaj.org/article/c953a2b8329f400782de8297d4e8e508 PLoS Neglected Tropical Diseases, Vol 8, Iss 10, p e3275 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003275 2022-12-30T23:19:51Z BACKGROUND: Leishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock Protein 90 (HSP90)-specific inhibitor, reduces L. (L.) amazonensis infection in vitro. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis. METHODOLOGY/PRINCIPAL FINDINGS: Exposure of axenic L. (V.) braziliensis promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to L. (V.) braziliensis-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O(-2)) or inflammatory mediators such as TNF-α, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated in vivo, employing BALB/c mice infected with L. braziliensis. In this model, 17-AAG treatment resulted in smaller skin lesions and parasite counts were also significantly reduced. Lastly, 17-AAG showed a similar effect to amphotericin B regarding the ability to reduce parasite viability. CONCLUSION/SIGNIFICANCE: 17-AAG effectively inhibited the growth of L. braziliensis, both in vitro and in vivo. Given the chronicity of L. (V.) braziliensis infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 8 10 e3275 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Diego M Santos Antonio L O A Petersen Fabiana S Celes Valeria M Borges Patricia S T Veras Camila I de Oliveira Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND: Leishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock Protein 90 (HSP90)-specific inhibitor, reduces L. (L.) amazonensis infection in vitro. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis. METHODOLOGY/PRINCIPAL FINDINGS: Exposure of axenic L. (V.) braziliensis promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to L. (V.) braziliensis-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O(-2)) or inflammatory mediators such as TNF-α, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated in vivo, employing BALB/c mice infected with L. braziliensis. In this model, 17-AAG treatment resulted in smaller skin lesions and parasite counts were also significantly reduced. Lastly, 17-AAG showed a similar effect to amphotericin B regarding the ability to reduce parasite viability. CONCLUSION/SIGNIFICANCE: 17-AAG effectively inhibited the growth of L. braziliensis, both in vitro and in vivo. Given the chronicity of L. (V.) braziliensis infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis. |
format |
Article in Journal/Newspaper |
author |
Diego M Santos Antonio L O A Petersen Fabiana S Celes Valeria M Borges Patricia S T Veras Camila I de Oliveira |
author_facet |
Diego M Santos Antonio L O A Petersen Fabiana S Celes Valeria M Borges Patricia S T Veras Camila I de Oliveira |
author_sort |
Diego M Santos |
title |
Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
title_short |
Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
title_full |
Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
title_fullStr |
Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
title_full_unstemmed |
Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. |
title_sort |
chemotherapeutic potential of 17-aag against cutaneous leishmaniasis caused by leishmania (viannia) braziliensis. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0003275 https://doaj.org/article/c953a2b8329f400782de8297d4e8e508 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 10, p e3275 (2014) |
op_relation |
http://europepmc.org/articles/PMC4207694?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003275 https://doaj.org/article/c953a2b8329f400782de8297d4e8e508 |
op_doi |
https://doi.org/10.1371/journal.pntd.0003275 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
8 |
container_issue |
10 |
container_start_page |
e3275 |
_version_ |
1766340671411585024 |