Salicylate is a signaling molecule in plants. It also exhibits signaling activities in mammalian cells. Experimental and clinical data indicate that salicylates have a spectrum of activities, including antithrombotic, anti-inflammatiory, anti-neoplastic, and anti-microbial actions. Aspirin, a synthetic derivative of salicylic acid, is widely used in treating human diseases. The antithrombotic action is unique to aspirin and not shared by other salicylates as only aspirin possesses the property to acetylate COX-1. Other actions of salicylates are attributed to salicylate, a major metabolite of aspirin in vivo. Salicylates are active in controlling inflammation and tumor growth by altering gene expressions. They suppress the expression of pro-inflammatory genes by inhibiting the DNA binding activities of transcription activators such as NF-κB, AP-1 and C/EBPβ. Their actions appear to be concentration related. Salicylates at high concentrations non-selectively inhibit the binding activities of diverse transactivators. At pharmacological concentrations, salicylates inhibit C/EBPβ binding and C-Rel. Transcriptional suppression by salicylates is mediated by kinase inhibition. Salicylates at high concentrations inhibit diverse classes of kinases and, paradoxically, activate some kinases. However, at micromolar concentrations, salicylates inhibit p90 ribosomal S6 kinase (RSK) and p70 S6 kinase (S6K). The mechanism by which salicylates inhibit kinases is unclear. We propose that salicylates at mM concentrations non-selectively inhibit ATP binding to kinases. At micromolar concentrations, they inhibit substrate binding to a selective family of kinases including RSK and S6K. Further structural analysis will yield valuable information which will be useful in designing new anti-inflammatory and anti-neoplastic drugs.
Date:
2007-11
Relation:
Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry. 2007 Nov;6(4):278-292.
