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

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 
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.
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Author:Ivonne Wobst, Lisa Ebert, Kerstin Birod, Marthe-Susanna Wegner, Marika Hoffmann, Dominique Jeanette Thomas, Carlo Federico Angioni, Michael J. Parnham, Dieter Steinhilber, Irmgard Tegeder, Gerd Geisslinger, Sabine Grösch
URN:urn:nbn:de:hebis:30:3-441278
DOI:http://dx.doi.org/10.3390/ijms18010068
ISSN:1422-0067
ISSN:1661-6596
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=28042832
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Contributor(s):Johannes Haybäck
Document Type:Article
Language:English
Date of Publication (online):2017/04/20
Year of first Publication:2016
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/04/20
Tag:MRP4; PGE2; cPLA2; flurbiprofen
Volume:18
Issue:Art. 68
Pagenumber:16
First Page:1
Last Page:16
Note:
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
HeBIS PPN:421370696
Institutes:Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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