DEVELOPMENT OF A NEW MOLECULAR TARGETING THERAPY FOR ESOPHAGEAL CANCER USING CYCLIN DEPENDENT KINASE (CDK) INHIBITOR

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Purpose: Flavopiridol is a synthetic flavone that has shown an antitumor effect against several cancers. Here, we investigated the in vitro effect of flavopiridol alone and the combined effect of low-dose flavopiridol plus radiation on esophageal squamous cell carcinoma cell lines. Experimental design: Esophageal squamous cell carcinoma cell lines (TE8, TE9, and KE4) were exposed to flavopiridol (0.05-400 nM) for 48 h. Cytotoxicity was evaluated by the MTT assay, cell cycle distribution was determined by flow cytometry, and cyclin Dl, Bcl-2, and Rb protein expression was detected by Western blotting. The effect of 0.05 nM flavopiridol combined with radiation was determined by the clonogenic assay. Results: The IC_<50> was approximately 110-250 nM. Exposure to 0.05 nM flavopiridol for 48 h increased the G_2 /M population, while 300 nM increased the G_1 population. At a concentration of 300 nM, nuclear fragmentation and chromatin condensation were observed in all three cell lines. Exposure to 300 nM flavopiridol decreased the levels of cyclin Dl and Rb protein in all three cell lines and bcl-2 protein was also decreased in TE8 and KE4 cells. Moreover, exposure to 0.05 nM flavopiridol slightly decreased the levels of cyclin D1, Rb, and Bcl-2 protein in KE4 cells. A significant synergistic effect of 0.05 nM flavopiridol and radiation was observed for all three cell lines. Conclusion: Combined treatment with low-dose flavopiridol and radiation showed a synergistic effect on esophageal squamous cell carcinoma. Administration of a low dose of flavopiridol could be a potent new therapeutic approach for improving the efficacy of radiotherapy against esophageal cancer.