Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats.
The biological role of the peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARgamma ligands have been found to inhibit mammary carcinogenesis in rodents, the effects on colon tumorigenesis are controversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPARalpha and PPARgamma) on colitis and an early phase of colitis-related colon carcinogenesis in male F344 rats. In the first experiment, gastric gavage of troglitazone (PPARgamma ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPARalpha ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextran sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic mucosa. In the second experiment, dietary administration (0.01 or 0.05% in diet) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxymethane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced formation of aberrant crypts foci, which are precursor lesions for colon carcinoma. In the third experiment, dietary administration (0.01% in diet for 6 weeks) of pioglitazone (PPARgamma ligand), troglitazone, and bezafibrate effectively suppressed DSS/AOM-induced ACF. Administration of both ligands significantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPARalpha and PPARgamma) can inhibit the early stages of colon tumorigenesis with or without colitis.
Tanaka
T
T
Department of Pathology, Kanazawa Medical University, Ishikawa, Japan. takutt@kanazawa-med.ac.jp
Kohno
H
H
Yoshitani
S
S
Takashima
S
S
Okumura
A
A
Murakami
A
A
Hosokawa
M
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000037:antagonists & inhibitors / Q000633:toxicity; D001629:Bezafibrate / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000037:antagonists & inhibitors / Q000633:toxicity; D006133:Growth Substances / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D009697:Nucleolus Organizer Region / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016622:Silver Staining; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D000077288:Troglitazone
D016588:Anticarcinogenic Agents; D002839:Chromans; D006133:Growth Substances; D008024:Ligands; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C000604007:TFF2 protein, human; C082495:TFF3 protein, human; C099037:TFF3 protein, rat; C000604008:Tff2 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D016264:Dextran Sulfate; D000077288:Troglitazone; D001397:Azoxymethane; D001629:Bezafibrate