title: Different COX-independent effects of the COX-2 inhibitors etoricoxib and lumiracoxib.
abstract: Etoricoxib and lumiracoxib are both highly selective COX-2 inhibitors. This drug class has recently been linked to severe side effects in particular within the cardiovascular system. The underlying signal transduction pathway is not clarified at the moment but different COX-independent mechanisms might contribute to wanted and unwanted effects of these drugs. Here, we investigated COX-2-independent effects of etoricoxib and lumiracoxib. Both inhibited the activation of the transcription factor NF-kappaB, but had no effects on activation of the AP-1 subunits c-jun and c-fos. On the other hand, activation of the transcription factor CREB was dose-dependently inhibited only by etoricoxib. Together with NF-kappaB-inhibition this might contribute to the reduced protein expression of the pro-inflammatory proteins COX-2 and iNOS. In contrast, lumiracoxib did not influence CREB activation and showed no effect on iNOS and COX-2 protein expression. In conclusion, we showed that etoricoxib and lumiracoxib have different COX-independent mechanisms which may be of clinical relevance.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. e.niederberger@em.uni-frankfurt.de
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.forename: Christine
authors.initials: C
authors.lastname: Manderscheid
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives; D015232:Dinoprostone / Q000096:biosynthesis; D000077613:Etoricoxib; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009930:Organic Chemicals / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016861:Cyclooxygenase Inhibitors; D016328:NF-kappa B; D009573:Nitrites; D009930:Organic Chemicals; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D013450:Sulfones; D018808:Transcription Factor AP-1; D004008:Diclofenac; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C473384:lumiracoxib; D000077613:Etoricoxib