Tamoxifen in the treatment of leishmaniasis: evaluation of efficacy in combination therapy schemes and study of the antileishmanial mechanism of action

Abstract

The treatment of all clinical forms of leishmaniasis relies on costly parenteral administered drugs with multiple undesirable effects. We have recently described the antileishmanial activity of tamoxifen, a drug already in use for the treatment of breast cancer for over 30 years. Tamoxifen has been shown to be effective in several in vivo experimental models of visceral and cutaneous leishmaniasis. A new clinical use of tamoxifen would be much strengthened by the characterization of its activity in combination therapy, as to the efficacy and undesirable effects. To progress in the understanding and characterization of this new alternative for leishmaniasis chemotherapy we aim at: evaluating the efficacy of tamoxifen when used in combination with meglumine antimoniate, amphotericin B or miltefosine in vitro and in vivo; testing the effectiveness of tamoxifen in experimental models of cutaneous leishmaniasis when applied topically, alone and in combination with the classical antileishmanial agents; determining the activity of a library of molecules structurally related to estrogen receptor modulators against the parasite in vitro, searching for more active and specific drugs; studying the metabolism of sphingolipids in tamoxifen treated promastigotes, aiming at defining possible molecular targets of its antileishmanial activity. (AU)