In vitro and in vivo inhibitory effect of three Cox-2 inhibitors and epithelial-to-mesenchymal transition in human bladder cancer cell lines

• Published in: British journal of cancer 2011-07, Vol.105 (3), p.393-402
• Main Authors: Adhim, Z, Matsuoka, T, Bito, T, Shigemura, K, Lee, K-M, Kawabata, M, Fujisawa, M, Nibu, K, Shirakawa, T
• Format: Article
• Language: English
• Subjects: 631/80/84/2176; 631/92/436/2388; 692/308/575; 692/699/67/589/1336; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Cadherins - metabolism; Cancer Research; Cell Dedifferentiation; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclooxygenase 2 Inhibitors - pharmacology; Drug Resistance; Epidemiology; Epithelial-Mesenchymal Transition; Etodolac - pharmacology; Humans; Medical sciences; Mice; Mice, Nude; Molecular Medicine; Nephrology. Urinary tract diseases; Oncology; Translational Therapeutics; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms; Urinary tract. Prostate gland; Vimentin - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.262

Background: Although the anti-tumour effect of cyclooxygenase-2 (Cox-2) inhibitors in invasive bladder cancer has been confirmed, its mechanisms of action are unclear. Recently, the concept of an epithelial-to-mesenchymal transition (EMT) promoting carcinoma progression has been suggested, and a key feature of the EMT is the downregulation of E-cadherin. In this study, we investigated the effect of Cox-2 inhibitors on reversal EMT and tumour growth inhibition in bladder cancer cells. Methods: We used three Cox-2 inhibitors, etodolac, celecoxib and NS-398 and three human bladder cancer cell lines, T24, 5637 and KK47, in this study. T24 xenograft tumour mouse model was used in the in vivo study. Results: Within the clinical drug concentrations, only etodolac showed the in vitro growth inhibition in T24 not in the other cell lines. Etodolac reduced SNAIL mRNA and vimentin cell surface expression, and induced E-cadherin mRNA and E-cadherin cell surface expression, in T24. Etodolac also most strongly inhibited the cell migration of T24 in vitro and showed the highest tumour growth inhibition in T24 tumour in vivo . Conclusion: Etodolac at clinical doses exhibited induced in vitro and in vivo anti-tumour effects and reversal effect of EMT in T24. These results suggest that etodolac is a good candidate for an anti-tumour or chemopreventive reagent for high-grade bladder cancer.