Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania

Author(s)

Trinconi, Cristiana T. ^[1] ; Miguel, Danilo C. ^{[2, 1]} ; Silber, Ariel M. ^[1] ; Brown, Christopher ^[3] ; Mina, John G. M. ^[3] ; Denny, Paul W. ^[3] ; Heise, Norton ^[4] ; Uliana, Silvia R. B. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, Av Prof Lineu Prestes 1374, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Biol Anim, Campinas, SP - Brazil

^[3] Univ Durham, Dept Biosci, Stockton Rd, Durham DH1 3LE - England

^[4] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Av Carlos Chagas Filho 373, BR-21941902 Rio De Janeiro, RJ - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE; v. 8, n. 3, p. 475-487, DEC 2018.
• Web of Science Citations: 1

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 {[}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. (AU)

• FAPESP's process: 15/09080-2 - Evaluation of candidate drugs for the treatment of Leishmaniasis in Brazil
• Grantee: Silvia Reni Bortolin Uliana
• Support type: Regular Research Grants
• FAPESP's process: 11/18858-6 - TAMOXIFEN AS AN ANTI-LEISHMANIAL DRUG: ACTIVITY IN COMBINED THERAPEUTIC SCHEMES AND STUDY OF THE MECHANISM OF ACTION
• Grantee: Cristiana de Melo Trinconi Tronco
• Support type: Scholarships in Brazil - Doctorate