Enhancement of gefitinib-induced growth inhibition by Marsdenia tenacissima extract in non-small cell lung cancer cells expressing wild or mutant EGFR.
Enhancement of gefitinib-induced growth inhibition by Marsdenia tenacissima extract in non-small cell lung cancer cells expressing wild or mutant EGFR.
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DOI：
10.1186/1472-6882-14-165
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发表时间：
2014-05-22
影响因子：
--
通讯作者：
Li PP
中科院分区：
文献类型：
--
作者：
Han SY;Ding HR;Zhao W;Teng F;Li PP
非小细胞肺癌（NSCLC）表达高水平的表皮生长因子受体（EGFR）。吉非替尼（易瑞沙）已在携带EGFR突变或化疗难治的NSCLC患者中显示出临床疗效。然而，大多数NSCLC患者携带野生型EGFR，对吉非替尼的反应有限。因此，仍然需要开发新的有效的NSCLC治疗干预措施。本课题组前期研究表明通光藤提取物（MTE）可恢复吉非替尼对耐药NSCLC细胞的疗效，但MTE对吉非替尼敏感的NSCLC细胞是否与耐药细胞作用相同尚不清楚。针对两种具有突变型或野生型EGFR状态的敏感NSCLC细胞系生成吉非替尼和MTE的剂量反应曲线。使用IC 50和组合指数方法评价MTE和吉非替尼对细胞生长的三种不同顺序组合。流式细胞仪检测细胞凋亡和细胞周期。采用Western blotting法研究MTE联合吉非替尼对细胞分子网络反应的影响。与耐药NSCLC细胞不同，我们的研究结果显示，低细胞毒性剂量的MTE（8 mg/ml）与三种不同的时间表联合使用可协同或相加地增强吉非替尼的生长抑制作用。其中MTE → MTE +吉非替尼治疗效果最好。MTE可明显促进EGFR突变型（HCC 827）和野生型（H292）NSCLC细胞的细胞周期阻滞和凋亡。Western blotting结果显示MTE → MTE +吉非替尼处理进一步增强了吉非替尼对细胞生长和凋亡途径如ERK 1/2和PI 3 K/Akt/mTOR的抑制作用。这种组合还阻断了EGFR和c-Met的活化，它们彼此具有串扰。与吉非替尼耐药NSCLC细胞不同，单独的MTE也显示出对敏感细胞中EGFR相关细胞信号通路的某些意想不到的调节。我们的研究结果表明，无论EGFR状态如何，MTE都是一种很有前途的草药，可以提高吉非替尼在NSCLC中的疗效。然而，MTE在吉非替尼敏感和耐药NSCLC细胞中的作用为何不同，还需进一步研究。
Non-small cell lung cancer (NSCLC) expressed high levels of epidermal growth factor receptor (EGFR). Gefitinib (Iressa) has demonstrated clinical efficacy in NSCLC patients harboring EGFR mutations or refractory to chemotherapy. However, most of NSCLC patients are with wild type EGFR, and showed limited response to gefitinib. Therefore, to develop new effective therapeutic interventions for NSCLC is still required. Our previous study showed Marsdenia tenacissima extract (MTE) restored gefitinib efficacy in the resistant NSCLC cells, but whether MTE acts in the gefitinib-sensitive NSCLC cells is the same as it in the resistant one is unknown. Dose response curves for gefitinib and MTE were generated for two sensitive NSCLC cell lines with mutant or wild type EGFR status. Three different sequential combinations of MTE and gefitinib on cell growth were evaluated using IC50 and Combination Index approaches. The flow cytometric method was used to detect cell apoptosis and cell cycle profile. The impact of MTE combined with gefitinib on cell molecular network response was studied by Western blotting. Unlike in the resistant NSCLC cells, our results revealed that low cytotoxic dose of MTE (8 mg/ml) combined gefitinib with three different schedules synergistically or additively enhanced the growth inhibition of gefitinib. Among which, MTE → MTE + gefitinib treatment was the most effective one. MTE markedly prompted cell cycle arrest and apoptosis caused by gefitinib both in EGFR mutant (HCC827) and wild type of NSCLC cells (H292). The Western blotting results showed that MTE → MTE + gefitinib treatment further enhanced the suppression of gefitinib on cell growth and apoptosis pathway such as ERK1/2 and PI3K/Akt/mTOR. This combination also blocked the activation of EGFR and c-Met which have cross-talk with each other. Unlike in gefitinib-resistant NSCLC cells, MTE alone also demonstrated certain unexpected modulation on EGFR related cell signal pathways in the sensitive cells. Our results suggest that MTE is a promising herbal medicine to improve gefitinib efficacy in NSCLC regardless of EGFR status. However, why MTE acted differently between gefitinib-sensitive and -resistant NSCLC cells needs a further research.
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