Astrid Stefanie Kahnt, Carlo Angioni, Tamara Göbel, Bettina Hofmann, Jessica Roos, Svenja Dorothea Steinbrink, Florian Rörsch, Dominique Jeanette Thomas, Gerd Geisslinger, Kai Zacharowski, Sabine Grösch, Dieter Steinhilber, Thorsten Jürgen Maier
- 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.
MetadatenAuthor: | Astrid Stefanie KahntORCiDGND, Carlo AngioniORCiD, Tamara GöbelORCiD, Bettina HofmannORCiDGND, Jessica RoosGND, Svenja Dorothea SteinbrinkGND, Florian RörschGND, Dominique Jeanette ThomasORCiDGND, Gerd GeisslingerORCiDGND, Kai ZacharowskiORCiDGND, Sabine GröschORCiDGND, Dieter SteinhilberORCiDGND, Thorsten Jürgen MaierGND |
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URN: | urn:nbn:de:hebis:30:3-738751 |
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DOI: | https://doi.org/10.3389/fphar.2021.782584 |
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ISSN: | 1663-9812 |
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Parent Title (English): | Frontiers in pharmacology |
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Publisher: | Frontiers Media |
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Place of publication: | Lausanne |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2022/01/21 |
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Date of first Publication: | 2022/01/21 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2023/06/02 |
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Tag: | ABC transporter; eicosanoid; inflammation; lipoxygenase inhibitor; multidrug resistance protein 4; prostaglandin |
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Volume: | 12 |
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Issue: | art. 782584 |
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Article Number: | 782584 |
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Page Number: | 13 |
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First Page: | 1 |
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Last Page: | 13 |
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Note: | This work was supported by Deutsche Forschungsgemeinschaft (DFG) GRK 1172 and SFB 1039; Merck KGaA, Darmstadt, Germany; the “Landes Offensive zur Entwicklung Wissenschaftlich Ökonomischer Exzellenz” LOEWE-LiFF and LOEWE-TMP, Fraunhofer IME-TMP and the German Excellence Cluster “Cardio-Pulmonary System” (ECCPS). |
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Institutes: | Biochemie, Chemie und Pharmazie |
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| Medizin |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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| 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 - CC BY - Namensnennung 4.0 International |
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