Pro-inflammatory mechanisms of a non-steroidal anti-inflammatory drug

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-inflammatory therapeutic agents. They work by inhibiting the cyclooxygenase enzymes, thereby blocking the production of inflammatory prostaglandins. NSAIDs have also been used as chemoprotective agents for cancer, although the mechanism by which they achieve this chemoprotective effect is thought to be independent of cyclooxygenase inhibition. Adamson et al. [1xDiclofenac antagonizes peroxisome proliferator-activated receptor γ signalling. Adamson, D.J.A. et al. Mol. Pharmacol. 2001; 61: 7–12Crossref | Scopus (60)See all References][1] now identify the peroxisome proliferator activated receptor γ (PPAR-γ) 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 PPAR-γ agonist cis-parinaric acid (CPA) to measure the binding affinity of NSAIDs with PPAR-γ. The NSAID diclofenac was shown to have fourfold greater affinity for PPAR-γ than the putative endogenous ligand, which indicates that a single oral dose of diclofenac would produce sufficiently high serum concentrations to allow interaction with PPAR-γ. PPAR-γ 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 PPAR-γ-mediated gene regulation by diclofenac was measured using a transactivation assay. Diclofenac was found to be a partial agonist of PPAR-γ, producing a twofold activation of gene expression (compared with a 6.6-fold activation elicited by the PPAR-γ agonist rosiglitazone). When added in combination with rosiglitazone, diclofenac lowered reporter gene activation by sub-saturating levels, but not saturating levels, of rosiglitazone, the expected effects of a competitive partial agonist. In physiological tests, diclofenac was also shown to inhibit adipocyte differentiation induced by PPAR-γ and released a PPAR-γ-dependent cancer cell line from growth arrest induced by rosiglitazone.Many NSAIDs are freely available and widely used for the treatment of pain. Therefore, it is important to understand the mechanisms by which these compounds mediate 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 PPAR-γ signalling. If this is the case, diclofenac would be expected to block the anti-inflammatory effects of PPAR-γ, and in support of this theory there is evidence suggesting that some NSAIDs have pro-inflammatory responses. Finally, the authors point out that because PPAR-γ has also become a possible target for cancer chemoprotective agents, not all NSAIDs would necessarily be beneficial in this area.