RRC ID 65868
Author Egashira I, Takahashi-Yanaga F, Nishida R, Arioka M, Igawa K, Tomooka K, Nakatsu Y, Tsuzuki T, Nakabeppu Y, Kitazono T, Sasaguri T.
Title Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β-catenin signaling pathway.
Journal Cancer Sci
Abstract We previously reported that celecoxib, a selective 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 analog that does not inhibit COX-2, has also been reported to have an antitumor 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. 2,5-Dimethylcelecoxib suppressed cell proliferation and inhibited T-cell factor 7-like 2 expression with almost the same strength as celecoxib. 2,5-Dimethylcelecoxib also inhibited the T-cell factor-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 treatment with celecoxib and DM-celecoxib markedly reduced the number and size of the carcinomas without showing toxicity. These results suggest that the central mechanism for the anticancer 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 a better lead compound candidate than celecoxib for the development of novel anticancer drugs.
Volume 108(1)
Pages 108-115
Published 2017-1-1
DOI 10.1111/cas.13106
PMID 27761963
PMC PMC5276826
MeSH Animals Blood Cell Count Body Weight / drug effects Celecoxib / blood Celecoxib / pharmacology* Celecoxib / therapeutic use Cell Line, Tumor DNA Glycosylases / deficiency DNA Glycosylases / genetics Female Humans Intestinal Neoplasms / drug therapy* Intestinal Neoplasms / metabolism Intestinal Neoplasms / pathology* Male Mice Oxidative Stress / drug effects Proteolysis / drug effects Pyrazoles / blood Pyrazoles / pharmacology* Pyrazoles / therapeutic use Sulfonamides / blood Sulfonamides / pharmacology* Sulfonamides / therapeutic use TCF Transcription Factors / metabolism Transcription Factor 7-Like 2 Protein / metabolism Transcription, Genetic / drug effects Wnt Proteins / metabolism* Wnt Signaling Pathway / drug effects* beta Catenin / antagonists & inhibitors beta Catenin / metabolism*
IF 4.966
Human and Animal Cells HCT116(RCB2979)