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.