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Open AccessArticle

R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4

1
Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
2
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
3
Institute of Pharmaceutical Chemistry, ZAFES, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany
*
Author to whom correspondence should be addressed.
Marika Hoffmann was a co-worker at the Institute of Pharmaceutical Chemistry. She is sadly passed away.
Academic Editor: Johannes Haybaeck
Int. J. Mol. Sci. 2017, 18(1), 68; https://doi.org/10.3390/ijms18010068
Received: 23 November 2016 / Revised: 22 December 2016 / Accepted: 23 December 2016 / Published: 30 December 2016
(This article belongs to the Special Issue Pain and Inflammation)
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 cPLA 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. View Full-Text
Keywords: flurbiprofen; MRP4; cPLA2; PGE2 flurbiprofen; MRP4; cPLA2; PGE2
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MDPI and ACS Style

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. R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4. Int. J. Mol. Sci. 2017, 18, 68.

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