Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib.
Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.
Yamada
Y
Y
Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. y-yamada@cc.gifu-u.ac.jp
Yoshimi
N
N
Hirose
Y
Y
Hara
A
A
Shimizu
M
M
Kuno
T
T
Katayama
M
M
Qiao
Z
Z
Mori
H
H
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000494:pharmacology; D000068579:Celecoxib; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D009697:Nucleolus Organizer Region / Q000378:metabolism; D011230:Precancerous Conditions / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators; D051176:beta Catenin
D016588:Anticarcinogenic Agents; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D015534:Trans-Activators; D051176:beta Catenin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D001397:Azoxymethane