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 toS-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E₂ (PGE₂) in cancer or immune cell cultures and human extracellular fluid. Here, we show thatR-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2αto 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 ofR-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by whichR-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.
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. mail@iwobst.de.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Wobst
authors.affiliation: 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. ebert.lisa@web.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ebert
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. k.birod@med.uni-frankfurt.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Birod
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. marthewegner@me.com.
authors.forename: Marthe-Susanna
authors.initials: MS
authors.lastname: Wegner
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany. steinhilber@em.uni-frankfurt.de.
authors.forename: Marika
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. thomas@med.uni-frankfurt.de.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. Angioni@em.uni-frankfurt.de.
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.affiliation: 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. Michael.Parnham@ime.fraunhofer.de.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.affiliation: Institute of Pharmaceutical Chemistry, ZAFES, Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Str. 9, D-60438 Frankfurt, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. tegeder@em.uni-frankfurt.de.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. geisslinger@em.uni-frankfurt.de.|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. geisslinger@em.uni-frankfurt.de.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Institute for Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. groesch@em.uni-frankfurt.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
mesh_terms: D000072283:A549 Cells; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D005480:Flurbiprofen / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016718:Arachidonic Acid; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D005480:Flurbiprofen; D054513:Group IV Phospholipases A2; D053583:Interleukin-1beta; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014409:Tumor Necrosis Factor-alpha; C073492:ABCC4 protein, human; C516389:PLA2G4A protein, human
keywords: MRP4; PGE2; cPLA2; flurbiprofen