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1000 Titel
  • Inhibitors of Human 5-Lipoxygenase Potently Interfere With Prostaglandin Transport
1000 Autor/in
  1. Kahnt, Astrid S. |
  2. Angioni, Carlo |
  3. Göbel, Tamara |
  4. Hofmann, Bettina |
  5. Roos, Jessica |
  6. Steinbrink, Svenja D. |
  7. Rörsch, Florian |
  8. Thomas, Dominique |
  9. Geisslinger, Gerd |
  10. Zacharowski, Kai |
  11. Grösch, Sabine |
  12. Steinhilber, Dieter |
  13. Maier, Thorsten Jürgen |
1000 Erscheinungsjahr 2022
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2022-01-21
1000 Erschienen in
1000 Quellenangabe
  • 12:782584
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2022
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.3389/fphar.2021.782584 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8814463/ |
1000 Ergänzendes Material
  • https://www.frontiersin.org/articles/10.3389/fphar.2021.782584/full#h12 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 5-Lipoxygenase (5-LO) is the key enzyme in the formation of pro-inflammatory leukotrienes (LT) which play an important role in a number of inflammatory diseases. Accordingly, 5-LO inhibitors are frequently used to study the role of 5-LO and LT in models of inflammation and cancer. Interestingly, the therapeutic efficacy of these inhibitors is highly variable. Here we show that the frequently used 5-LO inhibitors AA-861, BWA4C, C06, CJ-13,610 and the FDA approved compound zileuton as well as the pan-LO inhibitor nordihydroguaiaretic acid interfere with prostaglandin E2 (PGE2) release into the supernatants of cytokine-stimulated (TNFα/IL-1β) HeLa cervix carcinoma, A549 lung cancer as well as HCA-7 colon carcinoma cells with similar potencies compared to their LT inhibitory activities (IC50 values ranging from 0.1–9.1 µM). In addition, AA-861, BWA4C, CJ-13,610 and zileuton concentration-dependently inhibited bacterial lipopolysaccharide triggered prostaglandin (PG) release into human whole blood. Western Blot analysis revealed that inhibition of expression of enzymes involved in PG synthesis was not part of the underlying mechanism. Also, liberation of arachidonic acid which is the substrate for PG synthesis as well as PGH2 and PGE2 formation were not impaired by the compounds. However, accumulation of intracellular PGE2 was found in the inhibitor treated HeLa cells suggesting inhibition of PG export as major mechanism. Further, experiments showed that the PG exporter ATP-binding cassette transporter multidrug resistance protein 4 (MRP-4) is targeted by the inhibitors and may be involved in the 5-LO inhibitor-mediated PGE2 inhibition. In conclusion, the pharmacological effects of a number of 5-LO inhibitors are compound-specific and involve the potent inhibition of PGE2 export. Results from experimental models on the role of 5-LO in inflammation and pain using 5-LO inhibitors may be misleading and their use as pharmacological tools in experimental models has to be revisited. In addition, 5-LO inhibitors may serve as new scaffolds for the development of potent prostaglandin export inhibitors.
1000 Sacherschließung
lokal prostaglandin
lokal lipoxygenase inhibitor
lokal inflammation
lokal multidrug resistance protein 4
lokal eicosanoid
gnd 4259409-1 Allgemeine Entzündungsreaktion
lokal ABC transporter
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/S2FobnQsIEFzdHJpZCBTLg==|https://frl.publisso.de/adhoc/uri/QW5naW9uaSwgQ2FybG8=|https://frl.publisso.de/adhoc/uri/R8O2YmVsLCBUYW1hcmE=|https://frl.publisso.de/adhoc/uri/SG9mbWFubiwgQmV0dGluYQ==|https://d-nb.info/gnd/1053809271|https://frl.publisso.de/adhoc/uri/U3RlaW5icmluaywgU3ZlbmphIEQu|https://frl.publisso.de/adhoc/uri/UsO2cnNjaCwgRmxvcmlhbg==|https://frl.publisso.de/adhoc/uri/VGhvbWFzLCBEb21pbmlxdWU=|https://frl.publisso.de/adhoc/uri/R2Vpc3NsaW5nZXIsIEdlcmQ=|https://frl.publisso.de/adhoc/uri/WmFjaGFyb3dza2ksIEthaQ==|https://frl.publisso.de/adhoc/uri/R3LDtnNjaCwgU2FiaW5l|https://frl.publisso.de/adhoc/uri/U3RlaW5oaWxiZXIsIERpZXRlcg==|https://orcid.org/0000-0003-3234-947X
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. Merck KGaA |
  3. LOEWE-LiFF |
  4. LOEWE-Zentrum für Translationale Medizin und Pharmakologie |
  5. Fraunhofer-Gesellschaft |
  6. Exzellenzcluster |
1000 Fördernummer
  1. GRK 1172, SFB 1039
  2. -
  3. -
  4. -
  5. -
  6. -
1000 Förderprogramm
  1. -
  2. -
  3. -
  4. -
  5. IME-TMP
  6. Cardio-Pulmonary System (ECCPS)
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer GRK 1172, SFB 1039
  2. 1000 joinedFunding-child
    1000 Förderer Merck KGaA |
    1000 Förderprogramm -
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer LOEWE-LiFF |
    1000 Förderprogramm -
    1000 Fördernummer -
  4. 1000 joinedFunding-child
    1000 Förderer LOEWE-Zentrum für Translationale Medizin und Pharmakologie |
    1000 Förderprogramm -
    1000 Fördernummer -
  5. 1000 joinedFunding-child
    1000 Förderer Fraunhofer-Gesellschaft |
    1000 Förderprogramm IME-TMP
    1000 Fördernummer -
  6. 1000 joinedFunding-child
    1000 Förderer Exzellenzcluster |
    1000 Förderprogramm Cardio-Pulmonary System (ECCPS)
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6431947.rdf
1000 Erstellt am 2022-03-03T14:00:30.405+0100
1000 Erstellt von 323
1000 beschreibt frl:6431947
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet Wed Mar 16 07:31:25 CET 2022
1000 Objekt bearb. Wed Mar 16 07:30:58 CET 2022
1000 Vgl. frl:6431947
1000 Oai Id
  1. oai:frl.publisso.de:frl:6431947 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

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