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R-flurbiprofen traps prostaglandins within cells by inhibition of multidrug resistance-associated protein-4

 
: Wobst, I.; Ebert, L.; Birod, K.; Wegner, M.-S.; Hoffmann, M.; Thomas, D.; Angioni, C.; Parnham, M.J.; Steinhilber, D.; Tegeder, I.; Geisslinger, G.; Grösch, S.

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International journal of molecular sciences 18 (2017), No.1, 16 pp.
ISSN: 1422-0067
ISSN: 1661-6596
English
Journal Article, Electronic Publication
Fraunhofer IME ()

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.

: http://publica.fraunhofer.de/documents/N-434852.html