Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania.
Int J Parasitol Drugs Drug Resist
; 8(3): 475-487, 2018 12.
Article
en En
| MEDLINE
| ID: mdl-30399513
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 d161/180-IPC, t160/C180-IPC, d181/180-IPC and t160/200-IPC) and PIs (sn-1-O-(C180)alkyl -2-O-(C181)acylglycerol-3-HPO4-inositol and sn-1-O-(C180)acyl-2-O-(C181)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⯵M (95% CI 7.68-9.37), suggesting that this enzyme is most likely one of the targets for this compound in the parasites.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
/
3_ND
Problema de salud:
2_enfermedades_transmissibles
/
3_zoonosis
Asunto principal:
Tamoxifeno
/
Glicoesfingolípidos
/
Vías Biosintéticas
/
Leishmania
Idioma:
En
Revista:
Int J Parasitol Drugs Drug Resist
Año:
2018
Tipo del documento:
Article
País de afiliación:
Brasil