R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis.
Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Although R-etodolac treatment did not affect COX-2 expression, it significantly enhanced expression of E-cadherin in both neoplastic lesions and background mucosa (i.e., lesion-free colon). Thus, administration of R-etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS-induced colitis without exacerbation of the colitis. These results suggest that R-etodolac could be useful in the prevention of UC-associated neoplasia.
Second Department of Internal Medicine, Osaka Medical College, Takatsuki city, Osaka 569-8686, Japan.
Takuya
T
Inoue
Mitsuyuki
M
Murano
Yukiko
Y
Yoda
Takanori
T
Kuramoto
Kazuki
K
Kakimoto
Kumi
K
Ishida
Ken
K
Kawakami
Yosuke
Y
Abe
Eijiro
E
Morita
Naoko
N
Murano
Satoshi
S
Tokioka
Kentaro
K
Maemura
Eiji
E
Umegaki
Kazuhide
K
Higuchi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D017308:Etodolac / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D012720:Severity of Illness Index; D047368:Tumor Burden; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D015820:Cadherins; D017308:Etodolac; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2