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中国应用生理学杂志 ›› 2018, Vol. 34 ›› Issue (6): 524-529.doi: 10.12047/j.cjap.5685.2018.117

• 研究论文 • 上一篇    下一篇

Smac类似物Birinapant的抗肝癌作用及相关分子机制

蒋盼若, 柯瑞君, 朱明了, 楼恩哲, 谢佳庚, 陈佳玉   

  1. 绍兴文理学院医学院, 浙江 绍兴 312000
  • 收稿日期:2018-03-12 修回日期:2018-11-14 出版日期:2018-11-28 发布日期:2019-03-09
  • 通讯作者: 陈佳玉 E-mail:chenkc1969@163.com
  • 基金资助:
    国家自然科学基金资助项目(81402979);浙江省科技厅资助项目(2015C33270);浙江省卫生厅资助项目(2014KYA230);国家大学生创新创业训练计划项目(201810349028);浙江省大学生科技创新活动计划项目(2018R432016);绍兴市大学生创新项目(SXSDC201709)

Anti-hepatoma effects of Smac analogue Birinapant and its related molecular mechanism

JIANG Pan-ruo, KE Rui-jun, ZHU Ming-liao, LOU En-zhe, XIE Jia-geng, CHEN Jia-yu   

  1. Medical School, Shaoxing University, Shaoxing 312000, China
  • Received:2018-03-12 Revised:2018-11-14 Online:2018-11-28 Published:2019-03-09
  • Supported by:
    国家自然科学基金资助项目(81402979);浙江省科技厅资助项目(2015C33270);浙江省卫生厅资助项目(2014KYA230);国家大学生创新创业训练计划项目(201810349028);浙江省大学生科技创新活动计划项目(2018R432016);绍兴市大学生创新项目(SXSDC201709)

摘要: 目的:探讨Birinapant抗肝癌的作用及分子机制。方法:人肝癌细胞QGY-7701经终浓度为0、1、5、25和125 nmol/L的Birinapant作用24、48和72 h,各设3个复孔,检测细胞增殖活性,分析细胞凋亡率,观察细胞核型和线粒体膜电位变化,分析基因转录与表达水平,评价药物细胞毒性;同时,将4周龄雄性BALB/C小鼠随机分成5组,每组20只,腹股沟注射肝癌细胞QGY-7701,两天后各组皮下分别注射Birinapant(0、1、5、25和125 μg/kg),隔天注射一次,首次注射Birinapant后18 d,每组脱颈处死10只小鼠,取瘤组织称重,并记录各组剩余10只小鼠的存活期,观察Birinapant对荷瘤小鼠肝癌生长及生存期的影响。结果:与对照组(NC)比较,Birinapant处理组的细胞增殖显著受抑制、细胞凋亡率显著增加(P<0.01),出现细胞线粒体膜电位降低及核型改变,同时细胞内cIAP-1(cellular inhibitor of apoptosis protein 1)、cIAP-2(cellular inhibitor of apoptosis protein 2)、ras、raf、mek、erk基因的表达显著下调(P<0.01),caspase-3和caspase-9基因的表达水平显著上调(P<0.01);与模型对照组(MG)比较,Birinapant处理组的荷瘤小鼠瘤组织生长速度显著减小且生存期延长(P<0.01)。结论:Birinapant通过抑制cIAP-1、cIAP-2和Ras-Raf-MEK-ERK通路蛋白的表达,激活线粒体介导的内源性凋亡,对肝癌有一定的抑制作用。

关键词: 肝癌, Smac类似物, Birinapant, 增殖, 凋亡, 小鼠

Abstract: Objective: To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms.Methods: Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 μg/kg) in each group after two days, once every other day.On 18th day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed.Results: Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (P<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (P<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (P<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (P<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (P<0.01).Conclusion: Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.

Key words: liver cancer, Smac analogue, Birinapant, proliferation, apoptosis, mice

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