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

Xie，Ya Jia1; Gao，Wei Na1,2; Wu，Qi Biao1; Yao，Xiao Jun1; Jiang，Ze Bo1; Wang，Yu Wei1; Wang，Wen Jun1; Li，Wei3; Hussain，Shahid1; Liu，Liang1; Leung，Elaine Lai Han1; Fan，Xing Xing1

2020-09-01

10.1016/j.phrs.2020.104934

PHARMACOLOGICAL RESEARCH   影响因子和分区

1043-6618

1096-1186

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 EGFR than EGFR, 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.

Apoptosis Chelidonine EGFR-AMPK pathway Gefitinib-resistant Mitochondrial injury NSCLC

SCI

英语

其他

Science and Technology Development Fund, Macau SAR[003/2018/A1]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000566437600018

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85086447099

Scopus

1.State Key Laboratory of Quality Research in Chinese Medicine,Macau Institute for Applied Research in Medicine and Health,Macau University of Science and Technology,Macau,China
2.Department of Chemistry,Southern University of Science and Technology,Shenzhen,China
3.TianJin NanKai Hospital,TianJin,China

Xie，Ya Jia,Gao，Wei Na,Wu，Qi Biao,et al. Chelidonine selectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells through the EGFR-AMPK pathway[J]. PHARMACOLOGICAL RESEARCH,2020,159.

Xie，Ya Jia.,Gao，Wei Na.,Wu，Qi Biao.,Yao，Xiao Jun.,Jiang，Ze Bo.,...&Fan，Xing Xing.(2020).Chelidonine selectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells through the EGFR-AMPK pathway.PHARMACOLOGICAL RESEARCH,159.

Xie，Ya Jia,et al."Chelidonine selectively inhibits the growth of gefitinib-resistant non-small cell lung cancer cells through the EGFR-AMPK pathway".PHARMACOLOGICAL RESEARCH 159(2020).