Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes

Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes

Author Miguel, Danilo C. Google Scholar
Yokoyama-Yasunaka, Jenicer K. U. Google Scholar
Andreoli, Walter K. Autor UNIFESP Google Scholar
Mortara, Renato A. Autor UNIFESP Google Scholar
Uliana, Silvia R. B. Google Scholar
Institution Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Objectives: 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 mu M, respectively. the drug was also effective against Leishmania ( Viannia) braziliensis, Leishmania (Leishmania) major, Leishmania ( Leishmania) chagasi and Leishmania (Leishmania) donovani with IC50 values ranging from 9.0 to 20.2 mu M. 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.
Keywords chemotherapy
pH
oestradiol
acridine orange
SNAFL-calcein
Language English
Date 2007-09-01
Published in Journal of Antimicrobial Chemotherapy. Oxford: Oxford Univ Press, v. 60, n. 3, p. 526-534, 2007.
ISSN 0305-7453 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press
Extent 526-534
Origin http://dx.doi.org/10.1093/jac/dkm219
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000249882200011
URI http://repositorio.unifesp.br/handle/11600/29980

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