Vol. 61, Issue 1, 7-12, January 2002

ACCELERATED COMMUNICATION
Diclofenac Antagonizes Peroxisome Proliferator-Activated Receptor- Signaling

Douglas J. A. Adamson, David Frew, Roger Tatoud, C. Roland Wolf, and Colin N. A. Palmer

Imperial Cancer Research Fund Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital, Dundee, Scotland, United Kingdom

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor- (PPAR), activation of which decreases cancer cell proliferation. NSAIDs have been shown to activate this receptor, but only at high concentrations. Here, we have examined binding of diclofenac to PPAR using a cis-parinaric acid displacement assay and studied the effect of diclofenac effect on PPAR trans-activation in a COS-1 cell reporter assay. Unexpectedly, diclofenac bound PPAR at therapeutic concentrations (K_i = 700 nM) but induced only 2-fold activation of PPAR at a concentration of 25 µM and antagonized PPAR trans-activation by rosiglitazone. This antagonism was overcome with increasing rosiglitazone concentrations, indicating that diclofenac is a partial agonist. No effect of diclofenac was seen without exogenous receptor, confirming that it was working through a PPAR-specific mechanism. This is the first description of an NSAID that can antagonize PPAR. In addition, this is the first time that an NSAID has been shown to bind this receptor at clinically meaningful concentrations. The physiological relevance of these findings was tested using adipocyte differentiation and cancer cell proliferation assays. Diclofenac decreased PPAR-mediated adipose cell differentiation by 60% and inhibited the action of rosiglitazone on the prostate cancer cell line, DU-145, allowing a 3-fold increase in proliferation. This work shows that standard doses of diclofenac may have pharmacodynamic interactions with rosiglitazone and this has therapeutic implications, both in the management of type 2 diabetes and during cancer treatment.