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JAC Advance Access published online on June 21, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm219
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Danilo C. Miguel1, Jenicer K. U. Yokoyama-Yasunaka1, Walter K. Andreoli2, Renato A. Mortara2 and Silvia R. B. Uliana1,*

1 Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-900 SP, Brazil 2 Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062 SP, Brazil

Received 8 February 2007; returned 6 April 2007; revised 7 May 2007; accepted 24 May 2007

* Corresponding author. Tel: +55-11-30917334; Fax: +55-11-30917417; E-mail: srbulian{at}icb.usp.br

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 µM, 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 µM. 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.

Key Words: chemotherapy , pH , oestradiol , Acridine Orange , SNAFL-calcein


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