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Dual inhibition of EGFR and MET by Echinatin retards cell growth and induces apoptosis of lung cancer cells sensitive or resistant to gefitinib
Author(s) -
Oh HaNa,
Lee MeeHyun,
Kim Eunae,
Kwak AhWon,
Seo JiHye,
Yoon Goo,
Cho SeungSik,
Choi JoonSeok,
Lee SangMyeong,
Seo KangSeok,
Chae JungIl,
Shim JungHyun
Publication year - 2020
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/ptr.6530
Subject(s) - gefitinib , cancer research , epidermal growth factor receptor , protein kinase b , cell growth , erbb3 , apoptosis , egfr inhibitors , lung cancer , tyrosine kinase , mapk/erk pathway , growth inhibition , pi3k/akt/mtor pathway , biology , kinase , pharmacology , signal transduction , medicine , cancer , microbiology and biotechnology , biochemistry
Patients with non‐small‐cell lung cancer (NSCLC) containing epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to tyrosine kinase inhibitor gefitinib; however, the treatment is less effective over time. Gefitinib resistance mechanisms include MET gene amplification. A therapeutic strategy targeting MET as well as EGFR can overcome resistance to gefitinib. In the present study we identified Echinatin (Ecn), a characteristic chalcone in licorice, which inhibited both EGFR and MET and strongly altered NSCLC cell growth. The antitumor efficacy of Ecn against gefitinib‐sensitive or –resistant NSCLC cells with EGFR mutations and MET amplification was confirmed by suppressing cell proliferation and anchorage‐independent colony growth. During the targeting of EGFR and MET, Ecn significantly blocked the kinase activity, which was validated with competitive ATP binding. Inhibition of EGFR and MET by Ecn decreases the phosphorylation of downstream target proteins ERBB3, AKT and ERK compared with total protein expression or control. Ecn induced the G2/M cell cycle arrest, and apoptosis via the intrinsic pathway of caspase‐dependent activation. Ecn induced ROS production and GRP78, CHOP, DR5 and DR4 expression as well as depolarized the mitochondria membrane potential. Therefore, our results suggest that Ecn is a promising therapeutic agent in NSCLC therapy.