TY  - JOUR
A1  - Kahnt, Astrid Stefanie
A1  - Angioni, Carlo
A1  - Göbel, Tamara
A1  - Hofmann, Bettina
A1  - Roos, Jessica
A1  - Steinbrink, Svenja Dorothea
A1  - Rörsch, Florian
A1  - Thomas, Dominique Jeanette
A1  - Geisslinger, Gerd
A1  - Zacharowski, Kai
A1  - Grösch, Sabine
A1  - Steinhilber, Dieter
A1  - Maier, Thorsten Jürgen
T1  - Inhibitors of human 5-lipoxygenase potently interfere with prostaglandin transport
T2  - Frontiers in pharmacology
N2  - 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.
KW  - prostaglandin
KW  - lipoxygenase inhibitor
KW  - multidrug resistance protein 4
KW  - inflammation
KW  - ABC transporter
KW  - eicosanoid
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73875
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-738751
SN  - 1663-9812
N1  - 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).
VL  - 12
IS  - art. 782584
SP  - 1
EP  - 13
PB  - Frontiers Media
CY  - Lausanne
ER  -