Inhibition of chemically induced skin carcinogenesis by sulindac is independent of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta).
Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-beta (PPARbeta), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARbeta either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARbeta in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARbeta-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARbeta-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE(2) and PGI(2). Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARbeta. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARbeta by COX-derived metabolites potentiates chemically induced skin carcinogenesis.
Kim
Dae J
DJ
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, 16802, USA.
Prabhu
K Sandeep
KS
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002273:Carcinogens; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D013467:Sulindac / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D047494:PPAR delta; D048068:PPAR-beta; D013467:Sulindac; D051546:Cyclooxygenase 2