Xu Yang, Luo Qiang, Lin Ting, Zeng Zhiping, Wang Guanghui, Zeng Dequan, Ding Rong, Sun Cuiling, Zhang Xiao-Kun, Chen Haifeng
School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, PR China.
School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, PR China; Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
PLoS One. 2014 Dec 8;9(12):e113479. doi: 10.1371/journal.pone.0113479. eCollection 2014.
U12, one of 20 derivatives synthesized from ursodeoxycholic acid (UDCA), has been found to have anticancer effects in liver cancer cell lines (SMMC-7721 and HepG2) and to protect normal liver cells from deoxycholic acid (DCA) damage (QSG-7701). Its anticancer mechanism was investigated using computer-aided network pharmacology and comparative proteomics. Results showed that its anti-malignancy activities were activated by mTOR/S6K1, cyclinD1/CDK2/4 and caspase-dependent apoptotic signaling pathways in hepatocellular carcinoma cells (HCC). The action of U12 may be similar to that of rapamycin. Animal testing confirmed that U12 exerted better anti-tumor activity than UDCA and had less severe side effects than fluorouracil (5-Fu). These observations indicate that U12 differs from UDCA and other derivatives and may be a suitable lead for the development of compounds useful in the treatment of HCC.
U12是从熊去氧胆酸（UDCA）合成的20种衍生物之一，已发现其对肝癌细胞系（SMMC-7721和HepG2）具有抗癌作用，并能保护正常肝细胞免受脱氧胆酸（DCA）损伤（QSG-7701）。采用计算机辅助网络药理学和比较蛋白质组学研究了其抗癌机制。结果表明，其抗恶性活性在肝癌细胞（HCC）中通过mTOR/S6K1、细胞周期蛋白D1/CDK2/4和半胱天冬酶依赖性凋亡信号通路被激活。U12的作用可能与雷帕霉素相似。动物试验证实，U12比UDCA具有更好的抗肿瘤活性，且副作用比氟尿嘧啶（5-Fu）轻。这些观察结果表明，U12不同于UDCA和其他衍生物，可能是开发用于治疗肝癌的化合物的合适先导物。
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