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  4. R-flurbiprofen traps prostaglandins within cells by inhibition of multidrug resistance-associated protein-4
 
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2017
Journal Article
Title

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

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 cPLA2a 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.
Author(s)
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.
Journal
International journal of molecular sciences  
Open Access
Link
Link
DOI
10.3390/ijms18010068
Additional full text version
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Language
English
Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie IME  
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