title: Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes.
abstract: OBJECTIVE
  This study was performed to investigate the activity of tamoxifen, an antioestrogen widely used in the treatment of breast cancer, against Leishmania.
  
  
  METHODS
  Drug activity was assessed in vitro against axenically grown promastigotes and amastigotes through cell counting or by measuring the cleavage of MTT, and against intracellular amastigotes by treating infected macrophage cultures and evaluating the number of intracellular parasites. Intravacuolar pH changes induced inside parasitophorous vacuoles of Leishmania (Leishmania) amazonensis-infected macrophages were evaluated using the fluorescent probes SNAFL-calcein and Acridine Orange.
  
  
  RESULTS
  Tamoxifen killed L. (L.) amazonensis promastigotes and amastigotes with 50% inhibitory concentrations (IC50) of 16.4 +/- 0.2 and 11.1 +/- 0.2 microM, respectively. The drug was also effective against Leishmania (Viannia) braziliensis, Leishmania (Leishmania) major, Leishmania (Leishmania) chagasi and Leishmania (Leishmania) donovani with IC(50) values ranging from 9.0 to 20.2 microM. Tamoxifen induced a rapid and long-lasting alkalinization of the vacuolar environment. We also provide evidence that tamoxifen is more effective against promastigotes and amastigotes at pH 7.5 when compared with cultures at pH 4.5.
  
  
  CONCLUSIONS
  Tamoxifen effectively kills several Leishmania species and its activity against the parasite is increased by a modulation of the host cell intravacuolar pH induced by the drug.
authors.affiliation: Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-900 SP, Brazil.
authors.forename: Danilo C
authors.initials: DC
authors.lastname: Miguel
authors.forename: Jenicer K U
authors.initials: JK
authors.lastname: Yokoyama-Yasunaka
authors.forename: Walter K
authors.initials: WK
authors.lastname: Andreoli
authors.forename: Renato A
authors.initials: RA
authors.lastname: Mortara
authors.forename: Silvia R B
authors.initials: SR
authors.lastname: Uliana
mesh_terms: D000468:Alkalies; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use*; D000981:Antiprotozoal Agents; D002470:Cell Survival / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use*; D014617:Vacuoles / Q000737:chemistry* / Q000187:drug effects / Q000469:parasitology
chemical_list: D000468:Alkalies; D018931:Antineoplastic Agents, Hormonal; D000981:Antiprotozoal Agents; D013629:Tamoxifen; D004958:Estradiol