Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE; v. 8, n. 3, p. 475-487, DEC 2018.
• Citações Web of Science: 1

Resumo

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)

• Processo FAPESP: 15/09080-2 - Avaliação de candidatos a fármacos para o tratamento de leishmaniose no Brasil
• Beneficiário: Silvia Reni Bortolin Uliana
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/18858-6 - Tamoxifeno como droga anti-leishmania: atividade em esquemas terapêuticos combinados e estudo do mecanismo de ação
• Beneficiário: Cristiana de Melo Trinconi Tronco
• Linha de fomento: Bolsas no Brasil - Doutorado