Journal
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
Volume 8, Issue 3, Pages 475-487Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2018.10.007
Keywords
Leishmania amazonensis; Tamoxifen; Sphingolipids; Inositolphosphorylceramide; Phosphatidylinositols; IPC synthase
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Funding
- Sao Paulo Research Foundation (FAPESP) [2015/09080-2]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [473343/2012-6]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Research Councils UK Grand Challenges Research Funder [MR/P027989/1, 2011/18858-6]
- FAPESP fellowship
- CNPq
- MRC [MR/P027989/1] Funding Source: UKRI
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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 [H-3]-sphingosine and myo-[H-3]-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-(C-18:0)alkyl -2-O-(C-18:1)acylglycerol-3-HPO4-inositol and sn-1-O-(C-18:0)acyl-2-O- (C-18:1)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 mu M (95% CI 7.68-9.37), suggesting that this enzyme is most likely one of the targets for this compound in the parasites.
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