Induction of Bim Expression Contributes to the Antitumor Synergy Between Sorafenib and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibitor CI-1040 in Hepatocellular Carcinoma
Induction of Bim Expression Contributes to the Antitumor Synergy Between Sorafenib and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibitor CI-1040 in Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-08-3294
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发表时间：
2009-09-15
影响因子：
11.5
通讯作者：
Chen, Ann-Lii
中科院分区：
文献类型：
--
作者：
Ou, Da-Liang;Shen, Ying-Chun;Chen, Ann-Lii
目的：索拉非尼已被证明可改善晚期肝细胞癌（HCC）患者的生存。本研究探讨加入丝裂原活化蛋白激酶/细胞外信号调节激酶（ERK）激酶（MEK）抑制剂CI-1040垂直阻断Raf/MEK/ERK通路是否可以提高sorafenib的疗效。实验设计：检测索拉非尼和CI-1040对HCC细胞系（Huh-7和Hep3B）和人脐血管内皮细胞（HUVEC）的生长抑制作用。采用中位效应分析测量潜在的协同生长抑制效应。流式细胞术检测细胞凋亡。Western blotting检测其对ERK磷酸化和凋亡调节蛋白水平的影响。在异种移植肝癌模型中检测索拉非尼和CI-1040的体内抗肿瘤活性。结果：索拉非尼与CI-1040联合用药可协同抑制ERK磷酸化，抑制细胞生长，诱导细胞凋亡。在HCC细胞和HUVECs中均发现Bim蛋白表达增加，且与ERK抑制程度相关。通过小干扰RNA敲低Bim表达，部分抵消了索拉非尼和CI-1040的协同促凋亡作用。在异种移植模型中，联合治疗对肿瘤生长的抑制明显优于任何单一药物。结论：CI-1040垂直阻断Raf/MEK/ERK信号通路可提高索拉非尼在HCC中的抗肿瘤作用。（临床癌症杂志2009；15(18):5820-8）
Purpose: Sorafenib has proved survival benefit for patients with advanced hepatocellular carcinoma (HCC). This study explored whether the efficacy of sorafenib can be improved by adding the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor CI-1040 to vertically block the Raf/MEK/ERK pathway.Experimental Design: The growth inhibitory effects of sorafenib and CI-1040 were tested in HCC cell lines (Huh-7 and Hep3B) and human umbilical vascular endothelial cells (HUVEC). The potential synergistic growth inhibitory effects were measured by median effect analysis. Apoptosis was measured by flow cytometry. The effects on ERK phosphorylation and levels of apoptosis regulatory proteins were measured by Western blotting. The in vivo antitumor activity of sorafenib and CI-1040 were tested in xenograft HCC models.Results: Combination of sorafenib and CI-1040 synergistically inhibited ERK phosphorylation and cell growth and induced apoptosis in both HCC cells and HUVECs. Increased expression of Bim protein, which correlated with the extent of ERK inhibition, was found in both HCC cells and HUVECs. Knockdown of Bim expression by small interfering RNA partially abrogated the synergistic proapoptotic effects of sorafenib and CI-1040. Combination therapy inhibited tumor growth significantly better than either single agent in the xenograft models.Conclusion: The antitumor effects of sorafenib in HCC can be improved by vertical blockade of Raf/MEK/ERK signaling with CI-1040. (Clin Cancer Res 2009;15(18):5820-8)