Ligand activation of peroxisome proliferator-activated receptor-beta/delta and inhibition of cyclooxygenase-2 enhances inhibition of skin tumorigenesis.
Ligand activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta 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 PPARbeta/delta-independent mechanisms. The present study examined the hypothesis that combining ligand activation of PPARbeta/delta 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 Pparbeta/delta-null mice. After 22 weeks, cohorts of both mouse lines were divided into four experimental groups: (1) control, (2) topical application of the PPARbeta/delta ligand GW0742, (3) dietary administration of the COX-2 inhibitor nimesulide, or (4) both GW0742 and nimesulide. Ligand activation of PPARbeta/delta 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 Pparbeta/delta-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 PPARbeta/delta with inhibition of COX-2 activity can inhibit chemically induced skin tumor progression by modulating differentiation.
Bility
Moses T
MT
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Zhu
Bokai
B
Kang
Boo H
BH
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007633:Keratins / Q000235:genetics; D007636:Keratoacanthoma / Q000201:enzymology / Q000517:prevention & control; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047494:PPAR delta / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010212:Papilloma / Q000201:enzymology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
D015127:9,10-Dimethyl-1,2-benzanthracene; D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D007633:Keratins; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D013449:Sulfonamides; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C012655:nimesulide