Dual cyclooxygenase and carbonic anhydrase inhibition by nonsteroidal anti-inflammatory drugs for the treatment of cancer

Among the class of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors or "coxibs" selectively inhibit the activity of the inducible isoform of cyclooxygenase. Moreover, there is emerging evidence that the sulfonamide-type coxibs, but not the methylsulfones, display an inhibitory activity also against several isoforms of human carbonic anhydrase (CA, EC 4.2.1.1). In this regard, celecoxib and valdecoxib, possessing a primary sulfonamide that binds to the zinc ion at the active site of the enzyme, are nanomolar inhibitors of the cancer-related hCA IX isoform. Also meloxicam and lornoxicam, NSAIDs belonging to the class of "oxicams", that contain a cyclic tertiary sulfonamide moiety, inhibit this isoform at low micromolar concentrations. The multiple pharmacological effects of the sulfonamide anti-inflammatory agents could be ascribed to the dual inhibition of CA and COX enzymes, supporting the evidence that inflammation and hypoxia pathways are involved in cancer onset and progression and suggesting that the antitumoral activity of these compounds should be further explored for their possible use in the polypharmacology of cancer prevention and therapy.