Combinatorial treatment of non-small-cell lung cancers with gefitinib and Ad.mda-7 enhances apoptosis-induction and reverses resistance to a single therapy
Combinatorial treatment of non-small-cell lung cancers with gefitinib and Ad.mda-7 enhances apoptosis-induction and reverses resistance to a single therapy
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DOI：
10.1002/jcp.20906
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发表时间：
2007-02-01
影响因子：
5.6
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Emdad, Luni;Lebedeva, Irina V.;Fisher, Paul B.
表皮生长因子受体(EGFR)的激活参与了非小细胞肺癌(NSCLC)的发病过程，吉非替尼是一种选择性可逆的EGFR抑制剂，对NSCLC患者有效。然而，临床对吉非替尼的耐药性是经常发生的，这突显了改进治疗策略的必要性。黑色素瘤分化相关基因-7(MDA-7)/白介素24(IL-24)(MDA-7/IL-24)通过不具复制能力的腺病毒(Ad.mda-7)表达，可选择性诱导肿瘤细胞凋亡。在这项研究中，在携带野生型EGFR(H-460和H-2030)或突变型EGFR(H-1650和H-1975)的NSCLC细胞系中，分析了Ad.mda-7单独感染或与吉非替尼联合感染的影响。H-2030和H-1650细胞对Ad.mda-7敏感，而H-460和H-1975细胞对Ad.mda-7的生长抑制作用较敏感，联合应用Gefitinib可逆转Ad.mda-7对H-460和H-1975细胞生长的抑制作用。这种联合作用增加了MDA-7/IL-24及其下游效应分子双链RNA活化蛋白激酶(PKR)的蛋白表达，促进了NSCLC细胞的凋亡诱导。单独给药时，抑制PKR可显著抑制Ad.mda-7诱导的细胞凋亡，但与吉非替尼合用时不能。联合治疗也加强了对EGFR信号的抑制。我们的研究结果表明，Ad.mda-7和吉非替尼联合治疗NSCLC可能是有益的，尤其是对临床使用的EGFR抑制剂表现出耐药性的患者。J.细胞。物理。210：549-559,2007。(C)2006年Wiley-Liss，Inc.
Activation of the epidermal growth factor receptor (EGFR) contributes to the pathogenesis of non-small-cell lung carcinomas (NSCLC) and gefitinib, a selective reversible EGFR inhibitor, is effective in treating patients with NSCLC. However, clinical resistance to gefitinib is a frequent occurrence highlighting the need for improved therapeutic strategies. Melanoma differentiation associated gene-7 (mda-7)/Interleukin-24 (IL-24) (mda-7/IL-24) displays cancer-selective apoptosis induction when delivered via a replication-incompetent adenovirus (Ad.mda-7). In this study, the effect of Ad.mda-7 infection, either alone or in combination with gefitinib, was analyzed in a panel of NSCLC cell lines carrying wild-type EGFR (H-460 and H-2030) or mutant EGFR (H-1650 and H-1975). While H-2030 and H-1650 cells were sensitive, H-460 and H-1975 cells were resistance to growth inhibition by Ad.mda-7, which was reversed by the combination of Ad.mda-7 and gefitinib. This combination increased MDA-7/IL-24 and downstream effector double-stranded RNA-activated protein kinase (PKR) protein expression, promoting apoptosis induction of NSCLC cells. Inhibition of PKR significantly inhibited apoptosis induction by Ad.mda-7 when administered alone but not when used in combination with gefitinib. The combination treatment also augmented inhibition of EGFR signaling. Our findings indicate that a combinatorial treatment with Ad.mda-7 and gefitinib may provide benefit in the treatment of NSCLC, especially in patients displaying resistance to clinically used EGFR inhibitors. J. Cell. Physiol. 210: 549-559, 2007. (c) 2006 Wiley-Liss, Inc.