天津医药

天津医药 ›› 2016, Vol. 44 ›› Issue (3): 298-301.doi: 10.11958/20150078

• 细胞与分子生物学 • 上一篇    下一篇

以c-Met为靶点的抗肿瘤系列化合物体内外药效筛选

王莹,张玉花,陈占法,刘玉刚   

  1. 1 河北工程大学医学院药理教研室（邮编 056002）；2河北工程大学图书馆；3 河北工程大学附属医院骨科
  • 收稿日期:2015-07-28 修回日期:2015-11-25 出版日期:2016-03-15 发布日期:2016-03-15
  • 通讯作者: 刘玉刚 E-mail:990060606@163.com
  • 作者简介:王莹（1984）， 女， 博士在读， 主要从事肿瘤药理学研究
  • 基金资助:
    邯郸市科学技术研究与发展计划项目

In vitro and in vivo pharmacodynamic screening of anticancer agents as c-Met inhibitor

WANG Ying, ZHANG Yuhua, CHEN Zhanfa, LIU Yugang   

  1. 1 Department of Pharmacology, Medical College of Hebei University of Engineering, Handan 056002, China;2 Hebei University of Engineering Library; 3 Department of Orthopedics of the Affiliated Hospital of Hebei University of Engineering
  • Received:2015-07-28 Revised:2015-11-25 Published:2016-03-15 Online:2016-03-15
  • Contact: LIU Yugang E-mail:990060606@163.com

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摘要： 目的　从8个LY系列肝细胞生长因子受体（c-Met）酪氨酸激酶抑制剂中筛选具有抗肿瘤活性的化合物，并进一步评价其体内外抗肿瘤作用。方法　首先采用均相时间分辨荧光技术（HTRF）对LY系列化合物进行初步筛选，观察它们对c-Met酪氨酸激酶的抑制作用；采用CCK8法观察筛选出的活性化合物在体外对人胃癌MKN-45、人神经胶质瘤U87MG、人肾癌Caki-1、人前列腺癌PC-3细胞株的增值抑制作用。建立人恶性胶质母细胞瘤U87MG裸小鼠移植瘤模型，考察活性化合物的抑瘤效果。结果　HTRF结果显示有4个活性较好的化合物（LY22，LY25，LY28，LY32），其中LY28对c-Met抑制作用优于阳性对照药Crizotinib；CCK8结果显示这些活性化合物对选用的4种靶细胞均有不同程度的抑制作用，其中LY28对肿瘤细胞增殖抑制作用最明显；裸小鼠移植瘤实验显示，LY28可显著抑制U87MG裸小鼠移植瘤的增殖，40 mg/kg LY28抑瘤率达到78.13%。结论　化合物LY28具有较好抗肿瘤活性，具有进一步研发的价值。

关键词: 肝细胞生长因子受体, 抗肿瘤, 活性筛选, 酪氨酸激酶抑制剂

Abstract: Objective To screen 8 series of LY compounds, which are c-Met tyrosine kinase inhibitors, and evaluate their anti-tumor effect in vitro and in vivo. Methods Preliminary screening was carried out by detecting the c-Met kinase phosphorylation inhibition activity of the compounds. CCK8 assay was adopted for secondary anti-tumor screen of the selected compounds using MKN-45, U87MG, Caki-1, PC-3 cell lines in vitro. The sc transplanted tumor model of U87MG cells in nude mice was established to evaluate the antitumor activity in vivo. Results Four compounds (LY22, LY25, LY28, LY32) with better activities were selected by HTRF method, where LY28 had better inhibitory effect on c-Met than Crizotinib. The above active compounds showed different degrees of inhibition on four kinds of target cells (MKN-45, U87MG, Caki-1 and PC-3) by CCK8 method, and the inhibition of LY28 was the most obvious. Antitumor activity in vivo showed that LY28 could significantly inhibited tumors growth in a dose-dependent manner. The tumors inhibition rate in high-dose of LY28 was 78.13%, close to 80.47% in Crizotinib group. Conclusion The compound LY28 has good antitumor activity in vitro and in vivo, which will be a new tyrosine kinase inhibitor.

Key words: c-Met, antitumor, activity screening, tyrosine kinase inhibitor