Journal Article

Ligand Activation of Peroxisome Proliferator–Activated Receptor-β/δ and Inhibition of Cyclooxygenase-2 Enhances Inhibition of Skin Tumorigenesis

Moses T. Bility, Bokai Zhu, Boo H. Kang, Frank J. Gonzalez and Jeffrey M. Peters

in Toxicological Sciences

Volume 113, issue 1, pages 27-36
Published in print January 2010 | ISSN: 1096-6080
Published online September 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp212
Ligand Activation of Peroxisome Proliferator–Activated Receptor-β/δ and Inhibition of Cyclooxygenase-2 Enhances Inhibition of Skin Tumorigenesis

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Ligand activation of peroxisome proliferator–activated receptor (PPAR)-β/δ and inhibition of cyclooxygenase-2 (COX-2) activity by nonsteroidal anti-inflammatory drugs can attenuate skin tumorigenesis. There is also evidence that attenuation of skin tumorigenesis by inhibition of COX-2 activity occurs through PPARβ/δ-independent mechanisms. The present study examined the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX-2 activity will cooperatively inhibit chemically induced skin tumor progression using both in vivo and ex vivo models. A two-stage chemical carcinogenesis bioassay was performed in wild-type and Pparβ/δ-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the PPARβ/δ ligand GW0742, (3) dietary administration of the COX-2 inhibitor nimesulide, or (4) both GW0742 and nimesulide. Ligand activation of PPARβ/δ did not influence skin tumor progression, while a modest decrease in skin tumor multiplicity was observed with dietary nimesulide. Interestingly, the combined treatment of GW0742 and nimesulide increased the efficacy of the decrease in papilloma multiplicity for 6 weeks in wild-type mice, but this effect was not found at later time points and was not found in similarly treated Pparβ/δ-null mice. Neoplastic keratinocyte lines cultured with GW0742 and nimesulide also exhibited enhanced inhibition of cell proliferation coincident with increased expression of Keratin messenger RNAs. Results from these studies support the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX-2 activity can inhibit chemically induced skin tumor progression by modulating differentiation.

Keywords: peroxisome proliferator–activated receptor; nonsteroidal anti-inflammatory drugs; cyclooxygenase-2; differentiation

Journal Article.  5425 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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