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Chelidonine selectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells through the EGFR-AMPK pathway.

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机构: [1]State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science andTechnology, Macau, SAR, PR China [2]Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong, PR China [3]TianJin NanKai Hospital, TianJin, PR China
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关键词: Gefitinib-resistant NSCLC Chelidonine Apoptosis Mitochondrial injury EGFR-AMPK pathway

摘要:
Tyrosine kinase inhibitors (TKIs) have been widely used for the clinical treatment of patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR. Unfortunately, due to the secondary mutation in EGFR, eventual drug-resistance is inevitable. Therefore, to overcome the resistance, new agent is urgently required. Chelidonine, extracted from the roots of Chelidonium majus, was proved to effectively suppress the growth of NSCLC cells with EGFR double mutation. Proteomics analysis indicated that mitochondrial respiratory chain was significantly inhibited by chelidonine, and inhibitor of AMPK effectively blocked the apoptosis induced by chelidonine. Molecular dynamics simulations indicated that chelidonine could directly bind to EGFR and showed a much higher binding affinity to EGFRL858R/T790M than EGFRWT, which demonstrated that chelidonine could selectively inhibit the phosphorylation of EGFR in cells with EGFR double-mutation. In vivo study revealed that chelidonine has a similar inhibitory effect like second generation TKI Afatinib. In conclusion, targeting EGFR and inhibition of mitochondrial function is a promising anti-cancer therapeutic strategy for inhibiting NSCLC with EGFR mutation and TKI resistance. Copyright © 2020. Published by Elsevier Ltd.

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出版当年[2019]版:
大类 | 2 区 医学
小类 | 1 区 药学
最新[2025]版:
大类 | 2 区 医学
小类 | 1 区 药学
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第一作者机构: [1]State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science andTechnology, Macau, SAR, PR China
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