天然产物
体内
细胞凋亡
微管蛋白
微管
细胞培养
肝细胞癌
细胞周期
细胞周期检查点
癌症研究
癌细胞
化学
药理学
体外
细胞毒性
生物
生物化学
癌症
细胞生物学
生物技术
遗传学
作者
Jun Yan,Qi-Zhen Zhuang,Zhenzhen Li,Yujuan Xiong,Min He,Cunmin Kang,Qiaoxuan Zhang,Liqiao Han,Enyu Liang,Hongcan Liu,Peifeng Ke,Xianzhang Huang
标识
DOI:10.1016/j.ejphar.2021.173975
摘要
Natural products are a large source of clinically effective antitumor drugs. Millepachine, a natural product derived from leguminous plants, was reported to display antitumor activity. In this study, the novel compound, (1H-indol-5-yl) (5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (MIL-1), was designed and synthesized by fusing millepachine and indole rings. MIL-1 exerted much better antitumor activity than millepachine, manifesting as a 24- to 201-fold increase in vitro cytotoxicity and a 2.4-fold increase in in vivo antitumor activity in hepatocellular cell lines-derived models. The immunofluorescence and HPLC detection revealed that MIL-1 was a potent microtubule targeting agent by interfering with the equilibrium of tubulin-microtubule dynamics and irreversibly binding to tubulin. MIL-1 displayed remarkable antitumor activity with an IC50 of 31-207 nM towards various human cancer cell lines derived from various organs and tissues, and it exerted no evidence of toxicity against normal cells. Mechanistic studies showed that MIL-1 arrested the cell cycle at G2/M phase and induced apoptosis by activating caspase-3 activity and reactive oxygen species (ROS) accumulation. Moreover, the superior antitumor effect of MIL-1 is worthy of further detailed study for the treatment of hepatocellular carcinoma (HCC).
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