Aurora激酶抑制剂ZLJ213抗人结肠癌的作用  

The anti-tumor activity and molecular mechanisms of an Aurora kinase inhibitor ZLJ213 in suppressing colon cancer growth

作　　者：周琬琪 张莉婧[2] 杨瀚泽 冯志强[2] 李燕 

机构地区：[1]中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室,北京100050 [2]中国医学科学院北京协和医学院药物研究所活性物质发现与适药性北京市重点实验室,北京100050

出　　处：《药学学报》2015年第7期854-860,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金青年基金资助项目(81102025)

摘　　要：ZLJ213是一个定向合成的Aurora激酶及血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)双靶点抑制剂。因此,预计它可以同时抑制肿瘤的增殖及新生血管的生成。本研究通过观察化合物ZLJ213在体外及体内的抗肿瘤作用,初步探讨其作用机制。研究结果显示,ZLJ213在体外对结肠癌细胞HCT116及SW48有较好的生长抑制作用,72 h的IC50分别为0.21μmol·L-1和0.28μmol·L-1;明显抑制肿瘤细胞集落的形成,使细胞周期阻滞在G2/M期,进而促进结肠癌细胞的凋亡。ZLJ213在100 mg·kg-1剂量下,可明显抑制人结肠癌HCT116裸鼠异体移植瘤的生长,抑制率达73.24%(按肿瘤体积计算)。ELISA方法检测到ZLJ213对p-Aurora A的IC50为0.258μmol·L-1。Western blot结果表明,0.08μmol·L-1 ZLJ213可明显抑制p-Aurora A、p-Histone H3及p-VEGFR的表达,同时下调周期相关蛋白Cyclin B水平,升高凋亡相关蛋白cleaved Caspase 3和cleaved PARP的水平,推断ZLJ213有可能是通过抑制Aurora及VEGFR的激酶活性而发挥其抗肿瘤作用。The aim of this study is to evaluate anti-tumor activities and mechanism of a novel kinase inhibitor ZLJ213 which targeted Aurora A and vascular endothelial growth factor receptor（VEGFR） in vitro and in vivo against human colon cancer. Results showed that ZLJ213 inhibited cell proliferation and induced cell cycle arrest and apoptosis of HCT116 and SW48 cell lines. In HCT116-derived xenograft, ZLJ213 dosed at 100 mg·kg-1 inhibited tumor growth by 73.24%. The IC50 of ZLJ213 on the expression of p-Aurora A was 0.258 μmol·L-1 analyzed by ELISA. Under the concentration of 0.08 μmol·L-1, ZLJ213 could inhibit the activities of Aurora A, Histone H3 and VEGFR of HCT116 and SW48 cell lines. Simultaneously, ZLJ213 induced activation of Caspase 3 and PARP cleavage. Above data suggested that ZLJ213 had the ability to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo in colon cancer, and down-regulate the expression of p-Aurora A and p-VEGFR. ZLJ213 might be a potential therapeutic agent against colon cancer.

关 键 词：2-(间环丁甲酰氨基苯胺基)-4-(2-环丙甲酰氨基-4-甲基噻唑-5-基)吡啶 结肠癌 抗肿瘤 AURORA激酶 血管内皮生长因子受体 

分 类 号：R965[医药卫生—药理学]