| 赵相轩,温 锋,毛晓楠.Iressa和Gleevec增敏Lexatumumab诱导肝癌细胞凋亡的研究[J].肿瘤学杂志,2016,22(10):844-849. |
| Iressa和Gleevec增敏Lexatumumab诱导肝癌细胞凋亡的研究 |
| The Study on Iressa/Gleevec-sensitized Lexatumumab-induced Apoptosis in Hepatocellular Carcinoma Cells |
| 投稿时间：2016-03-19 |
| DOI：10.11735/j.issn.1671-170X.2016.10.B013 |
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| 中文关键词: 酪氨酸激酶抑制剂 肝肿瘤 Bim Lexatumumab 细胞凋亡 |
| 英文关键词:tyrosine kinase inhibitor hepatocelluar cell carcinoma Bim Lexatumumab apoptosis |
| 基金项目:国家自然科学基金面上项目(31371425)；国家自然科学基金主任专项基金项目(31240025)；辽宁省自然科学基金项目(2013023056) |
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| 中文摘要: |
| 摘 要：［目的］ 研究酪氨酸激酶抑制剂Gleevec或Iressa增敏DR5激动剂Lexatumumab诱导肝癌细胞凋亡的效果及机制。［方法］ 体外培养肝癌LH86细胞株。分为对照组、TKI处理组、Lexatumumab 处理组、TKI+Lexatumumab处理组。用亚致死剂量的TKI或者Lexatumumab或者TKI+Lexatumumab同时处理细胞，通过荧光显微镜观察对照组和处理组细胞内细胞核凋亡形态变化情况。然后计数凋亡细胞，统计凋亡率。免疫印迹（Western blot）方法检测细胞凋亡标志性蛋白Caspase 3 切割条带在各组中的表达，促凋亡蛋白Bim、Bax以及抗凋亡蛋白在各处理组中的表达，以评估TK抑制作用对死亡受体信号通路诱导细胞凋亡的影响。［结果］在荧光显微镜下，可以观察到Gleevec、Iressa或Lexatumumab单独处理细胞不能够诱导LH86肝癌细胞核出现固缩凝聚现象。抑制剂Gleevec或Iressa 与Lexatumumab联合应用能够显著逆转诱导的肝癌细胞凋亡(Gleevec和Lexatumumab诱导凋亡率：39.23%，P<0.001；Iressa和Lexatumumab诱导凋亡率：37.5%，P<0.0001)。TKI和Lexatumumab诱导的细胞凋亡为Caspase依赖性。TKI和Lexatumumab诱导的细胞凋亡特异性诱导Bcl-2家族蛋白Bim上调。对Bax和Bcl-xl没有影响。［结论］ 肝癌细胞对Gleevec/Iressa或Lexatumumab单一制剂具有凋亡抗性。酪氨酸激酶抑制剂均能够增敏Lexatumumab诱导的细胞凋亡。这种联合诱导的细胞凋亡作用具有Caspase依赖性。TKI增敏的死亡受体介导的凋亡可能与促凋亡蛋白Bim上调有关。 |
| 英文摘要: |
| Abstract：［Objective］ To investigate the roles of tyrosine kinase inhibitors (TKI) Gleevec or Iressa in Lexatumumab-induced apoptosis in hepatocellular carcinoma cells. ［Methods］ Hepatocellular carcinoma (HCC) LH86 cells were cultured in vitro. We set up control group，tyrosine kinase inhibitor Gleevec or Iressa-treated group，Lexatumumab-treated group or either of two inhibitors plus Lexatumumab-treated group. Cells untreated or treated with various conditions were observed under microscope to show apoptosis by DNA fragmentation. Western blot was performed to detect apoptotic marker molecule Caspase 3 cleavage activation and Bcl-2 family protein expression. ［Results］ Low concentrations of Gleevec，Iressa or Lexatumumab did not induce DNA fragmentation in LH86 cells. However，the combination of TKI with Lexatumumab triggered massive apoptosis in these malignant cells (apoptosis ratio of Gleevec plus Lexatumumab：39.23%，P<0.001；Iressa plus Lexatumumab：37.5%，P<0.0001). In the presence of Caspase inhibitor，our results showed that Gleevec or Iressa and Lexatumumab combination treatment-induced apoptosis was Caspase dependent. We also found that TKI and lexatumumab combination treatment significantly increased proapoptotic protein Bim up-regulation，but not Bax. ［Conclusions］Tyrosine kinases inhibition is critical for death receptor-mediated apoptosis in HCC cells. |
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