NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma
NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma
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DOI：
10.1111/j.1478-3231.2011.02631.x
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发表时间：
2012-01-01
影响因子：
6.7
通讯作者：
Liang, Tingbo
中科院分区：
文献类型：
--
作者：
Chen, Wei;Shen, Xuning;Liang, Tingbo
背景资料：西妥昔单抗[一种表皮生长因子受体（EGFR）抑制剂]在直肠癌和非小细胞肺癌（NSCLC）中显示出有效性，但在肝细胞癌（HCC）的临床试验中仅表现出适度的有效性。STAT3被认为是HCC对抗肿瘤药物敏感性的决定因素，可能参与其中。目的：评价西妥昔单抗和NSC 74859（一种新型STAT3抑制剂）联合治疗EGFR和STAT3过表达肝癌细胞的疗效。方法：肝癌细胞系用西妥昔单抗、NSC 74859或两种药物联合处理。通过使用MTT测定法测定细胞活力和通过细胞计数测定增殖来评价处理的功效。使用Western印迹分析确定STAT3的表达和活化。我们使用siRNA介导的STAT3敲低或STAT3过表达策略评估了STAT3在单一和联合治疗中的作用。结果如下：HepG2和Huh-7细胞的pSTAT3水平低于SK-HEP1细胞，与SK-HEP1细胞相比，它们对西妥昔单抗治疗更敏感。尽管这些细胞系中没有一个对单独的NSC 74859敏感，但NSC 74859在所有三种细胞系中增强了西妥昔单抗的抗增殖作用。siRNA敲低STAT3增加了这些细胞系对西妥昔单抗的敏感性，而STAT3过表达则拮抗了这些作用。结论：在用NSC 74859和西妥昔单抗处理的肝癌细胞中增强的生长抑制表明西妥昔单抗抗性可能通过STAT3介导。使用EGFR和STAT3信号传导抑制剂的联合治疗保证了在体内条件下的进一步研究。
Background: Cetuximab [ an epidermal growth factor receptor (EGFR) inhibitor], which was shown to be effective in rectal and non-small cell lung cancers (NSCLCs), was only modestly effective in clinical trials of hepatocellular carcinoma (HCC). STAT3, which is thought to be a determinant of HCC sensitivity to antitumour drugs, may be involved. Aims: To evaluate the efficacy of combination therapy using cetuximab and NSC 74859 (a novel STAT3 inhibitor) in EGFR and STAT3 overexpressing hepatoma cells. Methods: Hepatoma cell lines were treated with cetuximab, NSC 74859 or a combination of both drugs. Efficacy of treatment was evaluated by determining cell viability using MTT assays and proliferation by cell counting. Expression and activation of STAT3 were determined using Western blot analysis. We evaluated the role of STAT3 in single and combination therapy using siRNA-mediated knock-down of STAT3 or STAT3 overexpression strategies. Results: HepG2 and Huh-7 cells, which had lower levels of pSTAT3 than SK-HEP1 cells, were more sensitive to cetuximab treatment when compared with SK-HEP1 cells. Although none of these cell lines was sensitive to NSC 74859 alone, NSC 74859 potentiated the antiproliferative effect of cetuximab in all three cell lines. siRNA knock-down of STAT3 increased the sensitivity of these cell lines to cetuximab, whereas STAT3 overexpression antagonized these effects. Conclusions: Enhanced growth inhibition in hepatoma cells treated with both NSC 74859 and cetuximab suggests that cetuximab resistance is probably mediated via STAT3. Combination therapy using both inhibitors of EGFR and STAT3 signalling warrants further investigation under in vivo condition.