Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands.
BACKGROUND
It is generally assumed that inflammatory bowel disease (IBD)-related carcinogenesis occurs as a result of chronic inflammation. We previously developed a novel colitis-related mouse colon carcinogenesis model initiated with azoxymethane (AOM) and followed by dextran sodium sulfate (DSS). In the present study we investigated whether a cyclooxygenase (COX)-2 inhibitor nimesulide and ligands for peroxisome proliferator-activated receptors (PPARs), troglitazone (a PPARgamma ligand) and bezafibrate (a PPARalpha ligand) inhibit colitis-related colon carcinogenesis using our model to evaluate the efficacy of these drugs in prevention of IBD-related colon carcinogenesis.


METHODS
Female CD-1 (ICR) mice were given a single intraperitoneal administration of AOM (10 mg/kg body weight) and followed by one-week oral exposure of 2% (w/v) DSS in drinking water, and then maintained on the basal diets mixed with or without nimesulide (0.04%, w/w), troglitazone (0.05%, w/w), and bezafibrate (0.05%, w/w) for 14 weeks. The inhibitory effects of dietary administration of these compounds were determined by histopathological and immunohistochemical analyses.


RESULTS
Feeding with nimesulide and troglitazone significantly inhibited both the incidence and multiplicity of colonic adenocarcinoma induced by AOM/DSS in mice. Bezafibrate feeding significantly reduced the incidence of colonic adenocarcinoma, but did not significantly lower the multiplicity. Feeding with nimesulide and troglitazone decreased the proliferating cell nuclear antigen (PCNA)-labeling index and expression of beta-catenin, COX-2, inducible nitric oxide synthase (iNOS) and nitrotyrosine. The treatments increased the apoptosis index in the colonic adenocarcinoma. Feeding with bezafibrate also affected these parameters except for beta-catenin expression in the colonic malignancy.


CONCLUSIONS
Dietary administration of nimesulide, troglitazone and bezafibrate effectively suppressed the development of colonic epithelial malignancy induced by AOM/DSS in female ICR mice. The results suggest that COX-2 inhibitor and PPAR ligands could serve as an effective agent against colitis-related colon cancer development.
Kohno
Hiroyuki
H
Department of Oncologic Pathology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. h-kohno@kanazawa-med.ac.jp
Suzuki
Rikako
R
Sugie
Shigeyuki
S
Tanaka
Takuji
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis; D001629:Bezafibrate / Q000494:pharmacology*; D001835:Body Weight; D002839:Chromans / Q000494:pharmacology*; D003092:Colitis / Q000150:complications* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009929:Organ Size; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*; D013696:Temperature; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002839:Chromans; D016861:Cyclooxygenase Inhibitors; D000960:Hypolipidemic Agents; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D013449:Sulfonamides; D045162:Thiazolidinediones; D014665:Vasodilator Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000077288:Troglitazone; C012655:nimesulide; D001629:Bezafibrate