Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer
Publication in refereed journal

替代計量分析
.

其它資訊
摘要Since cyclin‑dependent kinases 4/6 (CDK4/6) play pivotal roles in cell cycle regulation and are overexpressed in human skin cancers, CDK4/6 inhibitors are potentially effective drugs for skin cancer. In the present study, we present a mixed computational and experimental study attempting to repurpose approved small‑molecule drugs as dual CDK4/6 inhibitors for skin cancer treatment. We performed structure‑based virtual screening using the docking software idock, targeting an ensemble of CDK4/6 structures. We identified and selected nine compounds with significant predicted scores, and evaluated their cytotoxic effects in vitro in A375 and A431 human skin cancer cell lines. Rafoxanide was found to exhibit the highest cytotoxic effects (IC50: 1.09 µM for A375 and 1.31 µM for A431 cells). Consistent with the expected properties of CDK4/6 inhibitors, rafoxanide significantly increased the G1 phase population. Notably, we revealed that rafoxanide specifically decreased the expression of CDK4/6, cyclin D, retinoblastoma protein (Rb) and the phosphorylation of CDK4/6 and Rb. Furthermore, the anticancer effect of rafoxanide was demonstrated in vivo in BALB/C nude mice subcutaneously xenografted with human skin cancer A375 cells. Rafoxanide (40 mg/kg, i.p.) exhibited significant antitumor activity, comparable to that of oxaliplatin (5 mg/kg, i.p.). The combined administration of rafoxanide and oxaliplatin produced a synergistic therapeutic effect. To the best of our knowledge, the present study is the first to indicate that rafoxanide inhibits CDK4/6 activity and is a potential candidate drug for the treatment of human skin cancer.
著者Xinan Shi, Hongjian Li, Anhua Shi, Hong Yao, Kunbin Ke, Chao Dong, Ying Zhu, Yi Qin, Ying Ding, Yan Hong He, Xu Liu, Ling Li, Ling Lei, Qingshan Hai, Wei Chen, Kwong‑Sak Leung, Man‑Hon Wong, Hsiang‑Fu Kung, Marie Chia‑Mi Lin
期刊名稱Oncology Reports
出版年份2018
月份9
卷號40
期次3
出版社Spandidos Publications
出版地England
頁次1592 - 1600
國際標準期刊號1021-335X
電子國際標準期刊號1791-2431
語言英式英語

上次更新時間 2020-10-10 於 01:15