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
- 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.
MetadatenAuthor: | Ivonne Wobst, Lisa Ebert, Kerstin Birod, Marthe-Susanna WegnerORCiDGND, Marika Hoffmann, Dominique Jeanette ThomasORCiDGND, Carlo Federico AngioniORCiD, Michael J. ParnhamORCiDGND, Dieter SteinhilberORCiDGND, Irmgard TegederORCiDGND, Gerd GeisslingerORCiDGND, Sabine GröschORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-441278 |
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DOI: | https://doi.org/10.3390/ijms18010068 |
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ISSN: | 1422-0067 |
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ISSN: | 1661-6596 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28042832 |
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Parent Title (English): | International journal of molecular sciences |
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Publisher: | Molecular Diversity Preservation International |
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Place of publication: | Basel |
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Contributor(s): | Johannes Haybäck |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2017/04/20 |
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Year of first Publication: | 2016 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/04/20 |
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Tag: | MRP4; PGE2; cPLA2; flurbiprofen |
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Volume: | 18 |
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Issue: | Art. 68 |
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Page Number: | 16 |
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First Page: | 1 |
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Last Page: | 16 |
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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/). |
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HeBIS-PPN: | 421370696 |
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Institutes: | Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES) |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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