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Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania
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 wit...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216108/ https://www.ncbi.nlm.nih.gov/pubmed/30399513 http://dx.doi.org/10.1016/j.ijpddr.2018.10.007 |
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author | Trinconi, Cristiana T. Miguel, Danilo C. Silber, Ariel M. Brown, Christopher Mina, John G.M. Denny, Paul W. Heise, Norton Uliana, Silvia R.B. |
author_facet | Trinconi, Cristiana T. Miguel, Danilo C. Silber, Ariel M. Brown, Christopher Mina, John G.M. Denny, Paul W. Heise, Norton Uliana, Silvia R.B. |
author_sort | Trinconi, Cristiana T. |
collection | PubMed |
description | 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 [(3)H]-sphingosine and myo-[(3)H]-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-HPO(4)-inositol and sn-1-O-(C(18:0))acyl-2-O-(C(18:1))acylglycerol-3-HPO(4)-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 IC(50) 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. |
format | Online Article Text |
id | pubmed-6216108 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-62161082018-11-09 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. Int J Parasitol Drugs Drug Resist Regular article 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 [(3)H]-sphingosine and myo-[(3)H]-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-HPO(4)-inositol and sn-1-O-(C(18:0))acyl-2-O-(C(18:1))acylglycerol-3-HPO(4)-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 IC(50) 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. Elsevier 2018-10-24 /pmc/articles/PMC6216108/ /pubmed/30399513 http://dx.doi.org/10.1016/j.ijpddr.2018.10.007 Text en © 2018 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Regular article Trinconi, Cristiana T. Miguel, Danilo C. Silber, Ariel M. Brown, Christopher Mina, John G.M. Denny, Paul W. Heise, Norton Uliana, Silvia R.B. Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title | Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title_full | Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title_fullStr | Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title_full_unstemmed | Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title_short | Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania |
title_sort | tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in leishmania |
topic | Regular article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216108/ https://www.ncbi.nlm.nih.gov/pubmed/30399513 http://dx.doi.org/10.1016/j.ijpddr.2018.10.007 |
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