Pro-inflammatory mechanisms of a nonsteroidal anti-inflammatory drug

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-inflammatory therapeutic agents. They work by inhibiting the cyclo-oxygenase enzymes, so blocking the production of inflammatory prostaglandins. NSAIDs have also been used as chemoprotective agents for cancer, although the mechanism by which they achieve this is thought to be independent of cyclo-oxygenase inhibition. Adamson et al. [1xDiclofenac antagonizes peroxisome proliferator-activated receptor-γ signalling. Adamson, D.J.A. et al. Mol. Pharm. 2001; 61: 7–12Crossref | Scopus (56)See all References][1] now identify the peroxisome proliferator-activated receptor-γ (PPARγ) as a possible target for the analgesic diclofenac, and highlight some therapeutic implications for type 2 diabetes and cancer treatment.The authors used a spectrophotometric assay to measure the displacement of the PPARγ agonist, cis-parinaric acid (CPA), to measure the binding affinity of NSAIDs with the PPARγ receptor. The NSAID, diclofenac, was shown to have fourfold greater affinity for the PPARγ receptor than did the putative endogenous ligand, and a single oral dose of diclofenac would produce sufficiently high serum concentrations to allow interaction with PPARγ. PPARγ is a member of the nuclear hormone receptor family and, in conjunction with retinoid X receptors, regulates the transcription of various genes involved in lipid metabolism. It is an important therapeutic target for the treatment of diabetes and has recently been identified as a target for anticancer agents. The effect on PPARγ-mediated gene regulation by diclofenac was measured using a transactivation assay. Diclofenac was found to be a partial agonist of PPARγ, producing a twofold activation of gene expression (compared with a 6.6-fold activation for the PPARγ agonist rosiglitazone). When added in combination with rosiglitazone, diclofenac lowered reporter gene activation by subsaturating levels of rosiglitazone but not saturating levels, the expected effects of a competitive partial agonist. In physiological tests, diclofenac was also shown to inhibit adipocyte differentiation induced by PPARγ, and released a PPARγ-dependant cancer cell line from growth arrest induced by rosiglitazone.Many NSAIDs are freely available and widely used for the treatment of pain. It is important therefore to understand the mechanisms by which these compounds bring about their effects and how they might interact with other treatments. By inhibiting the effects of rosiglitazone, diclofenac would probably result in poor glucose control for diabetics taking a treatment of thiazolidnedione. The authors also suggest that diclofenac might inhibit endogenous PPARγ signalling. If this is the case, then it would be expected to block the anti-inflammatory effects of PPARγ, and in support of this, there is evidence suggesting that some NSAIDs have pro-inflammatory responses. Finally, the authors point out that, as PPARγ has also become a possible target for cancer chemoprotective agents, not all NSAIDs would necessarily be beneficial in this area.