Leishmania is not prone to develop resistance to tamoxifen.
Tamoxifen, an antineoplastic agent, is active in vitro and in vivo against the parasitic protozoa Leishmania. As part of our efforts to unravel this drug's mechanisms of action against the parasite and understand how resistance could arise, we tried to select tamoxifen-resistant Leishmania amazonensis. Three different strategies to generate tamoxifen resistant mutants were used: stepwise increase in drug concentration applied to promastigote cultures, chemical mutagenesis followed by drug selection and treatment of infected mice followed by selection of amastigotes. For amastigote selection, we employed a method with direct plating of parasites recovered from lesions into semi-solid media. Tamoxifen resistant parasites were not rescued by any of these methods. Miltefosine was used as a control in selection experiments and both stepwise selection and chemical mutagenesis allowed successful isolation of miltefosine resistant mutants. These findings are consistent with a multi-target mode of action to explain tamoxifen's leishmanicidal properties. Considering that drug resistance is a major concern in anti-parasitic chemotherapy, these findings support the proposition of using tamoxifen as a partner in drug combination schemes for the treatment of leishmaniasis.
['Coelho|Adriano C|AC|', 'Trinconi|Cristiana T|CT|', 'Senra|Luisa|L|', 'Yokoyama-Yasunaka|Jenicer K U|JK|', 'Uliana|Silvia R B|SR|']
D000818:Animals D000981:Antiprotozoal Agents D045744:Cell Line, Tumor D004305:Dose-Response Relationship, Drug D004351:Drug Resistance D005260:Female D006801:Humans D007891:Leishmania D007896:Leishmaniasis D051379:Mice D008807:Mice, Inbred BALB C D010767:Phosphorylcholine D020845:Selective Estrogen Receptor Modulators D013629:Tamoxifen
Tamoxifen Leishmania amazonensis Drug resistance Chemotherapy MNNG, N-methyl-N-nitroso-N′-nitroguanidine MT, miltefosine transporter NBD-PC, 2-(6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine PBS, phosphate buffered solution TM, tamoxifen