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Int. J. Mol. Sci. 2017, 18(1), 68; doi:10.3390/ijms18010068

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
Marika Hoffmann was a co-worker at the Institute of Pharmaceutical Chemistry. She is sadly passed away.
*
Author to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
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)
View Full-Text   |   Download PDF [2077 KB, uploaded 30 December 2016]   |  

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 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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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