基于诱导细胞凋亡产生显著抗癌活性的新型ent-贝壳杉烷型化合物CPUK02(英文)  

A new ent-kaurenoid derivative CPUK02 notably inhibits tumor growth through induction of apoptosis

作　　者：李洋[1] 王可[1] 张大永[1] 华维一[1] 吴晓明[1] 

机构地区：[1]中国药科大学药学院新药研究中心,南京210009

出　　处：《中国天然药物》2012年第6期429-435,共7页

基　　金：supported by the National Natural Science Foundation of China (NSFC) (Nos. 30973607 and 81172934)~~

摘　　要：CPUK02(15-羰基甜菊苷苄酯)是由甜菊苷半合成得到的一种新型化合物。采用多种体内体外模型验证了其抗肿瘤活性, 并初步探索了其抗肿瘤活性的作用机理。使用MTT法测试了该化合物的体外抗肿瘤活性, 发现CPUK02对于多种肿瘤细胞株都有显著地抑制作用; 此外, 对于肝癌细胞该化合物的作用相较于正常肝细胞有着显著地敏感性差异, 尤其在低浓度下,该化合物对癌细胞表现出较强的选择性。在多种人癌细胞小鼠异种移植瘤模型中, CPUK02表现出接近五氟尿嘧啶的抗肿瘤活性。同时使用Annexin/PI双染流式细胞术和DAPI染色的方法观察了CPUK02引起的肿瘤细胞的细胞形态学上的变化, 证明了该化合物确实可以诱导细胞凋亡, 该作用同时表现出明显的浓度依赖性。还使用了western blot探索了该化合物的抗肿瘤作用的机理, 发现该化合物可以作用于细胞凋亡的线粒体途径激活凋亡信号的级联转导。这些结果显示CPUK02是一种良好的抗肿瘤候选化合物, 并且有可能成为一种有前途的新型药物。CPUK02 （15-Oxosteviol benzyl ester） is a new semi-synthetic of stevioside. The anticancer activity was evaluated in several in vitro and in vivo models, and the mechanism of bioactivity studied. The anti-proliferation activity in vitro was tested by the MTT assay, which showed that CPUK02 strongly inhibited cell proliferation against a variety of human cancer cell lines. The human liver cancer cell line was significantly more sensitive than the normal liver cell line when CPUK02 was administered at low concentra- tion. In several mouse bearing human cancer xenograft models, CPUK02 demonstrated comparable anti-tumor effects to fluorouracil （5-FU）, but showed lower toxic effects. Annexin/PI double staining flow cytometry and DAPI staining experiments were used to observe the cellular morphological changes caused by CPUK02, which established that the compound induces cell apoptosis, and that the apoptotic effects appeared a dose dependent relationship. Western blot experiments were also carried out to explore the mechanism of this compound. It was found that this compound can activate the apoptosis signal cascade via the mitochondrial pathway in cells. These results indicate that CPUK02 may be a promising new compound with notable in vitro and in vivo anticancer activity. Further studies to investigate the effects on treating tumors are under way.

关 键 词：抗癌 ent-贝壳杉 体内体外筛选 凋亡 

分 类 号：R965[医药卫生—药理学]