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首页> 外文期刊>Biochemical Pharmacology >Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer cells and sensitizes the EGFR(L858R/T790M) cells to reversible EGFR tyrosine kinase inhibitors
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Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer cells and sensitizes the EGFR(L858R/T790M) cells to reversible EGFR tyrosine kinase inhibitors

机译：核心血管内血红素直接活跃在非小细胞肺癌细胞上，并使EGFR（L858R / T790M）细胞敏感到可逆的EGFR酪氨酸激酶抑制剂

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Metronomic vinorelbine (mVNR) has been described primarily as an antiangiogenic therapy, and no direct effects of mVNR on Non Small Cell Lung Cancer (NSCLC) cells has yet been demonstrated. The aims of this study were i) to establish the direct activity of mVNR on NSCLC cells either EGFR wt or EGFR(L858R/T790M), and ii) to quantify the synergism of the combination with reversible EGFR tyrosine kinase inhibitors (TKIs), investigating the underlying mechanism of action. Proliferation assays were performed on A-549 (wt EGFR(high)), H-292 (EGFR-wt), H-358 (EGFR-wt), H-1975 (EGFR(L858R/T790M)) NSCLC cell lines exposed to mVNR, its active metabolite deacetyl-VNR (D-VNR), gefitinib and erlotinib for 144 h treatments. The synergism between mVNR and EGFR TKIs was determined by the combination index (CI) in EGFR-wt and H-1975 NSCLC cells. Cyclin-D1 and ABCG2 genes expression and protein levels were measured by RT-PCR and ELISA assays, as well as the phosphorylation of ERK1/2 and Akt. Intracellular concentrations of EGFR TKIs and VNR were investigated with a mass spectrometry system. mVNR, and its active metabolite D-VNR, were extremely active on NSCLC cells, in particular on H-1975 (IC50 = 13.56 +/- 2.77 pM), resistant to TKIs. mVNR inhibited the phosphorylation of ERK1/2 and Akt and significantly decreased the expression of both cyclin-D1 and ABCG2 m-RNA and protein. The simultaneous combination of VNR and reversible EGFR TKIs showed a strong synergism on EGFR-wt NSCLC cells and on H1975 cells (e.g. CI = 0.501 for 50% of affected cells), increasing the intracellular concentrations of EGFR TKIs (e.g. + 50.5% vs. gefitinib alone). In conclusions, mVNR has direct effects on NSCLC cells and sensitizes resistant cells to EGFR TKIs, increasing their intracellular concentrations.
机译：致细胞组合血管列碱（MVNR）主要描述为抗血管生成治疗，并且尚未证明MVNR对非小细胞肺癌（NSCLC）细胞的直接影响。本研究的目的是i）在NSCLC细胞上建立MVNR的直接活性EGFR WT或EGFR（L858R / T790M）和II）以量化与可逆EGFR酪氨酸激酶抑制剂（TKI）的协同作用，调查行动的基础机制。在A-549（WT EGFR（高）），H-292（EGFR-WT），H-358（EGFR-WT），H-358（EGFR-WT），H-1975（EGFR（L858R / T790M））上进行增殖测定，暴露于MVNR，其活性代谢物Deaetyl-VNR（D-VNR），Gefitinib和Erlotinib为144小时治疗。 MVNR和EGFR TKI之间的协同作用由EGFR-WT和H-1975 NSCLC细胞中的组合指数（CI）测定。通过RT-PCR和ELISA测定和ERK1 / 2和AKT的磷酸化测量Cyclin-D1和ABCG2基因表达和蛋白质水平。用质谱系统研究了EGFR TKI和VNR的细胞内浓度。 MVNR及其活性​​代谢物D-VNR在NSCLC细胞上极为活跃，特别是在H-1975（IC50 = 13.56 +/- 2.77 PM）上，耐刺激。 MVNR抑制ERK1 / 2和AKT的磷酸化，并显着降低了细胞周期蛋白-D1和ABCG2M-RNA和蛋白质的表达。 VNR和可逆EGFR TKI的同时组合在EGFR-WT NSCLC细胞和H1975细胞上显示出强烈的协同作用（例如CI = 0.501，为50％受影响的细胞），增加EGFR TKI的细胞内浓度（例如+ 50.5％与单独的吉福尼布）。在结论中，MVNR对NSCLC细胞具有直接影响，并敏感抗性细胞至EGFR TKI，增加其细胞内浓度。

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