Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania

• DOI: 10.1016/j.ijpddr.2018.10.007
• Publication Date: 2018-10-24T06:36:59Z
• Authors: Cristiana T. Trin...; Danilo C. Miguel; Ariel M. Silber; Christopher Brown; John G.M. Mina; Paul W. Denny; Norton Heise; Silvia R.B. Uliana
• Keywords: IC50; Isoflavonoid

Previous work from our group showed that tamoxifen, an oral drug has been in use for the treatment of breast cancer over 40 years, is active both vitro and vivo against several species Leishmania, etiological agent leishmaniasis. Using a combination metabolic labeling with [3H]-sphingosine myo-[3H]-inositol, alkaline hydrolysis, HPTLC fractionations mass spectrometry analyses, we observed perturbation metabolism inositolphosphorylceramides (IPCs) phosphatidylinositols (PIs) after L. amazonensis promastigotes significant reduction biosynthesis major IPCs (composed d16:1/18:0-IPC, t16:0/C18:0-IPC, d18:1/18:0-IPC t16:0/20:0-IPC) PIs (sn-1-O-(C18:0)alkyl -2-O-(C18:1)acylglycerol-3-HPO4-inositol sn-1-O-(C18:0)acyl-2-O-(C18:1)acylglycerol-3-HPO4-inositol) species. Substrate saturation kinetics myo-inositol uptake analyses indicated inhibition inositol transport or availability were not main reasons reduced IPC PI tamoxifen treated parasites. An enzymatic assay was used to show able inhibit Leishmania synthase IC50 value 8.48 μM (95% CI 7.68-9.37), suggesting this enzyme most likely one targets compound