title: Celecoxib and 2,5-dimethylcelecoxib inhibit intestinal cancer growth by suppressing the Wnt/β-catenin signaling pathway.
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.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Egashira
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Nishida
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Arioka
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Igawa
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tomooka
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Department of Medicine and Clinical Science, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D000068579:Celecoxib / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics; D005260:Female; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C506698:2,5-dimethylcelecoxib; D011720:Pyrazoles; D013449:Sulfonamides; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000068579:Celecoxib
keywords: 2,5-dimethylcelecoxib; TCF7L2; Wnt/β-catenin signaling pathway; celecoxib; colon cancer