Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania

Trinconi, Cristiana T.; Miguel, Danilo C.; Silber, Ariel M.; Brown, Christopher; Mina, John G.M.; Denny, Paul W.; Heise, Norton; Uliana, Silvia R.B.

Abstract

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

Citation

Trinconi, C. T., Miguel, D. C., Silber, A. M., Brown, C., Mina, J. G., Denny, P. W., …Uliana, S. R. (2018). Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. International Journal for Parasitology: Drugs and Drug Resistance, 8(3), 475-487. https://doi.org/10.1016/j.ijpddr.2018.10.007

• Journal Article Type: Article
• Acceptance Date: Oct 23, 2018
• Online Publication Date: Oct 24, 2018
• Publication Date: Dec 1, 2018
• Deposit Date: Oct 26, 2018
• Publicly Available Date: Nov 12, 2018
• Journal: International Journal for Parasitology: Drugs and Drug Resistance
• Print ISSN: 2211-3207
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 3
• Pages: 475-487
• DOI: https://doi.org/10.1016/j.ijpddr.2018.10.007
• Public URL: https://durham-repository.worktribe.com/output/1344248