17-AAG kills intracellular Leishmania amazonensis while reducing inflammatory responses in infected macrophages

• Published in: PloS one Vol. 7; no. 11; p. e49496
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.11.2012; Public Library of Science (PLoS)
• Subjects: Animals; Autophagy; Autophagy - drug effects; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Biology; Cancer; Cancer treatment; Cell death; Cell Survival - drug effects; Clinical trials; Cytokines - biosynthesis; Developing countries; Drugs; Electron microscopy; Female; Heat shock proteins; Hsp90 protein; Inflammation; Inflammation - pathology; Inflammation Mediators - metabolism; Inhibitors; Interleukin 12; Interleukin 6; Intracellular; Intracellular Space - drug effects; Intracellular Space - parasitology; Kinases; Lactams, Macrocyclic - pharmacology; Lactams, Macrocyclic - therapeutic use; LDCs; Leishmania; Leishmania amazonensis; Leishmania mexicana - drug effects; Leishmania mexicana - growth & development; Leishmania mexicana - ultrastructure; Leishmaniasis; Leishmaniasis - drug therapy; Leishmaniasis - parasitology; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - parasitology; Macrophages - pathology; Male; Medical research; Medicine; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein 1; Myelin; Nitric oxide; Optical microscopy; Oxidation-Reduction - drug effects; Oxygen - metabolism; Parasite Load; Parasites; Parasites - drug effects; Parasites - growth & development; Parasites - ultrastructure; Parasitic diseases; Plasmodium; Rodents; Side effects; Superoxide; Tropical diseases; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vacuoles; Vector-borne diseases; Viability; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0049496

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. 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. 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.