Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology*
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DNA-Binding Proteins / antagonists & inhibitors
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Growth Substances / biosynthesis
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Heat-Shock Response / drug effects
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Isoenzymes / metabolism
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MAP Kinase Signaling System / drug effects
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Mice
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Models, Biological
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NF-kappa B / antagonists & inhibitors
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Pregnancy Proteins / biosynthesis
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Prostaglandin-Endoperoxide Synthases / metabolism
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Ribosomal Protein S6 Kinases / antagonists & inhibitors
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STAT1 Transcription Factor
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Trans-Activators / antagonists & inhibitors
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Transcription Factor AP-1 / antagonists & inhibitors
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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DNA-Binding Proteins
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Growth Substances
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Isoenzymes
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NF-kappa B
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Pregnancy Proteins
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Receptors, Cytoplasmic and Nuclear
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Trans-Activators
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Transcription Factor AP-1
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Ribosomal Protein S6 Kinases