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学科主题: 生命有机化学
题名: Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa
其他题名: 吉非替尼类似物V1801通过增量调节BH-3域蛋白Noxa诱导表皮生长因子受体 T790M包裹的肺癌细胞的凋亡
作者: Zhang B(张波) ; Jiao J(焦姣) ; LIU YING ; Guo LX(郭良霞) ; ZHOU BO ; Li GQ(李纲琴) ; Yao ZJ(姚祝军) ; Zhou GB(周光飚)
通讯作者: 姚祝军 ; 周光飚
刊名: PLoS One
发表日期: 2012-01-01
卷: 7, 期:11, 页:e48748
收录类别: SCI
部门归属: 中科院动物研究所; 中科院上海有机化学研究所; 中国科学院大学; 清华大学深圳研究生院
英文摘要: Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e. g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC.
语种: 英语
相关网址: 查看原文
内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/28513
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
Zhang B,Jiao J,LIU YING,et al. Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa[J]. PLoS One,2012,7(11):e48748.
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