The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells.
The green tea polyphenol EGCG potentiates the antiproliferative activity of c-Met and epidermal growth factor receptor inhibitors in non-small cell lung cancer cells.
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DOI：
10.1158/1078-0432.ccr-09-0109
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Cardelli JA
中科院分区：
文献类型：
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作者：
Milligan SA;Burke P;Coleman DT;Bigelow RL;Steffan JJ;Carroll JL;Williams BJ;Cardelli JA
c-Met 和表皮生长因子受体 (EGFR) 的激活可促进非小细胞肺癌 (NSCLC) 的生长和存活。特异性受体拮抗剂已在临床证明有效；然而，肿瘤常常对这些疗法产生耐药性。我们研究了 (-)-表没食子儿茶素-3-没食子酸酯 (EGCG) 在几种 NSCLC 细胞系中抑制细胞增殖以及 c-Met 受体和 EGFR 激酶激活的能力。研究了对 EGFR 拮抗剂厄洛替尼具有不同敏感性的 NSCLC 细胞系。使用 MTS 和集落形成测定来评估细胞生长。通过蛋白质印迹分析评估激酶激活。使用 EGCG、EGFR 拮抗剂厄洛替尼和 c-Met 抑制剂 SU11274 进行实验。还在使用 SCID 小鼠的异种移植模型中测试了拮抗剂。 EGCG 抑制厄洛替尼敏感和耐药细胞系的细胞增殖，包括 c-Met 过度表达和对厄洛替尼获得性耐药的细胞系。厄洛替尼/EGCG 组合比单独使用任一药物对细胞增殖和集落形成有更大的抑制作用。 EGCG 还完全抑制配体诱导的 c-Met 磷酸化并部分抑制 EGFR 磷酸化。 EGCG/厄洛替尼/SU11274的三重组合比EGCG与厄洛替尼产生更大的增殖抑制作用。最后，EGCG 和厄洛替尼的组合显着减慢了 H460 异种移植物的生长速度。在多种 NSCLC 细胞系中，包括对 EGFR 激酶抑制剂具有抗性的细胞系和过度表达 c-Met 的细胞系，EGCG 是一种有效的细胞增殖抑制剂，与 EGFR 抑制无关。因此，EGCG 可能是一种有用的药物，可作为其他抗癌药物的辅助剂进行研究。
Activation of the c-Met and epidermal growth factor receptors (EGFR) promotes growth and survival of non-small cell lung cancer (NSCLC). Specific receptor antagonists have demonstrated efficacy in the clinic; however, tumors often become resistant to these therapies. We have investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to inhibit cell proliferation, and c-Met receptor and EGFR kinase activation in several NSCLC cell lines. NSCLC cell lines with variable sensitivity to the EGFR antagonist erlotinib were studied. Cell growth was evaluated using MTS and colony formation assays. Kinase activation was assessed via western blot analysis. Experiments were conducted with EGCG, the EGFR antagonist erlotinib and the c-Met inhibitor SU11274. The antagonists were also tested in a xenograft model using SCID mice. EGCG inhibited cell proliferation in erlotinib sensitive and resistant cell lines, including those with c-Met overexpression and acquired resistance to erlotinib. The combination of erlotinib/EGCG resulted in greater inhibition of cell proliferation and colony formation than either agent alone. EGCG also completely inhibited ligand-induced c-Met phosphorylation and partially inhibited EGFR phosphorylation. The triple combination of EGCG/erlotinib/SU11274 resulted in a greater inhibition of proliferation than EGCG with erlotinib. Finally, the combination of EGCG and erlotinib significantly slowed the growth rate of H460 xenografts. EGCG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met. Therefore, EGCG might be a useful agent to study as an adjunct to other anti-cancer agents.