R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4.
Int J Mol Sci
; 18(1)2016 Dec 30.
Article
en En
| MEDLINE
| ID: mdl-28042832
ABSTRACT
R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance-associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Dinoprostona
/
Flurbiprofeno
/
Proteínas Asociadas a Resistencia a Múltiples Medicamentos
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2016
Tipo del documento:
Article
País de afiliación:
Alemania