Cyclooxygenase-independent actions of cyclooxygenase inhibitors.

Several studies have demonstrated unequivocally that certain nonsteroidal anti-inflammatory drugs (NSAIDs) such as sodium salicylate, sulindac, ibuprofen, and flurbiprofen cause anti-inflammatory and antiproliferative effects independent of cyclooxygenase activity and prostaglandin synthesis inhibition. These effects are mediated through inhibition of certain transcription factors such as NF-kappaB and AP-1. The respective NSAIDs might interfere directly with the transcription factors, but their effects are probably mediated predominantly through alterations of the activity of cellular kinases such as IKKbeta, Erk, p38 MAPK, or Cdks. These effects apparently are not shared by all NSAIDs, since indomethacin failed to inhibit NF-kappaB and AP-1 activation as well as Erk and Cdk activity. In contrast, indomethacin was able to activate PPARgamma, which was not affected by sodium salicylate or aspirin. The differences in cyclooxygenase-independent mechanisms may have consequences for the specific use of these drugs in individual patients because additional effects may either enhance the efficacy or reduce the toxicity of the respective compounds.