Adapalene inhibits the activity of cyclin-dependent kinase 2 in colorectal carcinoma
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摘要Cyclin-dependent kinase 2 (CDK2) has been reported to be overexpressed in human colorectal cancer; it is responsible for the G1-to-S-phase transition in the cell cycle and its deregulation is a hallmark of cancer. The present study was the first to use idock, a free and open-source protein-ligand docking software developed by our group, to identify potential CDK2 inhibitors from 4,311 US Food and Drug Administration-approved small molecular drugs with a re-purposing strategy. Among the top compounds identified by idock score, nine were selected for further study. Among them, adapalene (ADA; CD271,6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphtoic acid) exhibited the highest anti-proliferative effects in LoVo and DLD1 human colon cancer cell lines. Consistent with the expected properties of CDK2 inhibitors, the present study demonstrated that ADA significantly increased the G1-phase population and decreased the expression of CDK2, cyclin E and retinoblastoma protein (Rb), as well as the phosphorylation of CDK2 (on Thr-160) and Rb (on Ser-795). Furthermore, the anti-cancer effects of ADA were examined in vivo on xenograft tumors derived from DLD1 human colorectal cancer cells subcutaneously inoculated in BALB/C nude mice. ADA (20 mg/kg orally) exhibited marked anti-tumor activity, comparable to that of oxaliplatin (40 mg/kg), and dose-dependently inhibited tumor growth (P<0.05), while combined administration of ADA and oxaliplatin produced the highest therapeutic effect. To the best of our knowledge, the present study was the first to indicate that ADA inhibits CDK2 and is a potential candidate drug for the treatment of human colorectal cancer.
著者Shi XN, Li HJ, Yao H, Liu X, Li L, Leung KS, Kung HF, Lin MCM
期刊名稱Molecular Medicine Reports
出版年份2015
月份11
日期1
卷號12
期次5
出版社Spandidos Publications
頁次6501 - 6508
國際標準期刊號1791-2997
電子國際標準期刊號1791-3004
語言英式英語
關鍵詞adapalene; colorectal carcinoma; cycling-dependent kinase 2 inhibition
Web of Science 學科類別Medicine, Research & Experimental; Oncology; Research & Experimental Medicine

上次更新時間 2020-15-10 於 00:57