Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β-catenin signaling pathway

Summary

We previously reported that celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, strongly inhibited human colon cancer cell proliferation by suppressing the Wnt/β-catenin signaling pathway. 2,5-Dimethylcelecoxib (DM-celecoxib), a celecoxib analogue, which does not inhibit COX-2, has also been reported to have an anti-tumor effect. In the present study, we elucidated whether DM-celecoxib inhibits intestinal cancer growth, and its underlying mechanism of action. First, we compared the effect of DM-celecoxib with that of celecoxib on the human colon cancer cell lines HCT-116 and DLD-1. DM-celecoxib suppressed cell proliferation and inhibited TCF7L2 expression with almost same strength as celecoxib. DM-celecoxib also inhibited the TCF-dependent transcription activity and suppressed the expression of Wnt/β-catenin target gene products cyclin D1 and survivin. Subsequently, we compared the in vivo effects of celecoxib and DM-celecoxib using the Mutyh^-/- mouse model, in which oxidative stress induces multiple intestinal carcinomas. Serum concentrations of orally administered celecoxib and DM-celecoxib elevated to the levels enough to suppress cancer cell proliferation. Repeated administration of celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without exhibiting toxicity. These results suggest that the central mechanism for the anti-cancer effect of celecoxib derivatives is the suppression of the Wnt/β-catenin signaling pathway but not the inhibition of COX-2, and that DM-celecoxib might be might be a better lead compound candidate than celecoxib for the development of novel anti-cancer drugs.

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