Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells
Oridonin derivatives as potential anticancer drug candidates triggering apoptosis through mitochondrial pathway in the liver cancer cells
复制标题
冬凌草甲素衍生物作为潜在的抗癌药物候选者通过线粒体途径触发肝癌细胞凋亡
DOI：
10.1016/j.ejmech.2019.06.006
复制
发表时间：
2019-09-15
影响因子：
6.7
通讯作者：
Wan, Shengbiao
中科院分区：
文献类型：
--
作者：
Luo, Dongdong;Yi, Yujiao;Wan, Shengbiao
从香茶菜属植物中分离得到的天然对映贝壳杉烯二萜，冬凌草甲素的生物学功能已被深入研究。然而，由于其生物活性有限，其作用机制研究和临床应用受到限制。为了扩大冬凌草甲素的应用范围，探索其作用机制，本论文根据冬凌草甲素的结构设计合成了一系列衍生物。一些衍生物对四种癌细胞系的作用明显强于冬凌草甲素。特别是最有效的化合物20对高分化的HepG 2和低分化的PLC/PRF/5细胞的增殖有明显的抑制作用，其IC 50值分别为1.36 μ M和0.78 μ M，而冬凌草甲素的IC 50值分别为8.12 μ M和7.41 μ M。我们发现化合物20通过将细胞周期阻滞在G1期来抑制肝癌细胞增殖。此外，它还通过降低线粒体膜电位、增加细胞内活性氧水平和诱导凋亡相关蛋白的表达来诱导肝癌细胞凋亡。此外，化合物20显着抑制PLC/PRF/5异种移植瘤在裸小鼠中的生长，并且没有明显的毒性作用。总之，这些结果表明化合物20是肝癌治疗的有希望的先导物。(C)2019 Elsevier Masson SAS。All rights reserved.
The biological function of the natural ent-kaurene diterpenoid isolated from genus Isodon, oridonin, has been intensively studied. However, its mechanism studies and clinical applications were hampered by its moderate biological activities. In order to enlarge the applied range of oridonin and explore its mechanism of action, a series of derivatives were designed and synthesized based on the structure of oridonin. Some of the derivatives were significantly more potent than oridonin against four cancer cell lines. Especially, the most potent compound 20 markedly inhibited the proliferation of well differentiated HepG2 and poorly differentiated PLC/PRF/5 cells, with IC50 values as low as 1.36 mu M and 0.78 mu M respectively, while the IC50 values of oridonin are 8.12 mu M and 7.41 mu M. We found that compound 20 inhibited liver cancer cell proliferation via arresting cell cycle at G1 phase. Moreover, it induced liver cancer cell apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular reactive oxygen species level and inducing the expression of apoptosis-related proteins. Furthermore, compound 20 significantly inhibited growth of PLC/PRF/5 xenograft tumors in nude mice and had no observable toxic effect. Altogether, these results indicated that compound 20 is a promising lead for liver cancer therapeutics. (C) 2019 Elsevier Masson SAS. All rights reserved.