R-etodolac induces E-cadherin and suppresses colitis-related mouse colon tumorigenesis

Oncol Rep. 2010 Dec;24(6):1487-92. doi: 10.3892/or_00001009.


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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carcinoma / etiology*
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Carcinoma / prevention & control*
  • Colitis / chemically induced
  • Colitis / complications*
  • Colitis / genetics
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Etodolac / pharmacology*
  • Etodolac / therapeutic use
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Severity of Illness Index
  • Tumor Burden
  • Up-Regulation / drug effects


  • Antineoplastic Agents
  • Cadherins
  • Etodolac
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2