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-kappa B, 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-kappa B-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 NOS and COX-2 protein expression. In conclusion, we showed that etoricoxib and lumiracoxib have different COX-independent mechanisms which may be of clinical relevance. (c) 2006 Elsevier Inc. All rights reserved.