Therapeutic Discovery Chemoprevention of Chemically Induced Skin Tumorigenesis by Ligand Activation of Peroxisome Proliferator–Activated Receptor-b/d and Inhibition of Cyclooxygenase 2

Ligand activation of peroxisome proliferator–activated receptor-b/d (PPARb/d) and inhibition of cyclooxygenase-2 (COX2) activity by nonsteroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The present study examined the hypothesis that combining ligand activation of PPARb/d with inhibition of COX2 activity will increase the efficacy of chemoprevention of chemically induced skin tumorigenesis over that observed with either approach alone. To test this hypothesis, wildtype and Pparb/d-null mice were initiated with 7,12-dimethylbenz[a]anthracene (DMBA), topically treated with 12-O-tetradecanoylphorbol-13-acetate to promote tumorigenesis, and then immediately treated with topical application of the PPARb/d ligand GW0742, dietary administration of the COX2 inhibitor nimesulide, or both GW0742 and nimesulide. Ligand activation of PPARb/d with GW0742 caused a PPARb/d-dependent delay in the onset of tumor formation. Nimesulide also delayed the onset of tumor formation and caused inhibition of tumor multiplicity (46%) in wild-type mice but not in Pparb/d-null mice. Combining ligand activation of PPARb/d with dietary nimesulide resulted in a further decrease of tumor multiplicity (58%) in wild-type mice but not in Pparb/d-null mice. Biochemical and molecular analysis of skin and tumor samples show that these effects were due to the modulation of terminal differentiation, attenuation of inflammatory signaling, and induction of apoptosis through both PPARb/d-dependent and PPARb/d-independent mechanisms. Increased levels and activity of PPARb/d by nimesulide were also observed. These studies support the hypothesis that combining ligand activation of PPARb/d with inhibition of COX2 activity increases the efficacy of preventing chemically induced skin tumorigenesis as compared with either approach alone. Mol Cancer Ther; 9(12); 3267–77. 2010 AACR.