title: 17-AAG kills intracellular Leishmania amazonensis while reducing inflammatory responses in infected macrophages.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Laboratório de Patologia e Biointervenção, Fundação Oswaldo Cruz-BA, Salvador, Bahia, Brazil.
authors.forename: Antonio Luis de Oliveira Almeida
authors.initials: AL
authors.lastname: Petersen
authors.forename: Carlos Eduardo Sampaio
authors.initials: CE
authors.lastname: Guedes
authors.forename: Carolina Leite
authors.initials: CL
authors.lastname: Versoza
authors.forename: José Geraldo Bomfim
authors.initials: JG
authors.lastname: Lima
authors.forename: Luiz Antônio Rodrigues
authors.initials: LA
authors.lastname: de Freitas
authors.forename: Valéria Matos
authors.initials: VM
authors.lastname: Borges
authors.forename: Patrícia Sampaio Tavares
authors.initials: PS
authors.lastname: Veras
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000469:parasitology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D007896:Leishmaniasis / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D059208:Parasite Load; D010271:Parasites / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure
chemical_list: D016227:Benzoquinones; D016207:Cytokines; D018836:Inflammation Mediators; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D010100:Oxygen