Dual inhibition of EGFR and MET by Echinatin retards cell growth and induces apoptosis of lung cancer cells sensitive or resistant to gefitinib. (7th November 2019)

• Record Type: Journal Article
• Authors: Oh, Ha‐Na; Lee, Mee‐Hyun; Kim, Eunae; Kwak, Ah‐Won; Seo, Ji‐Hye; Yoon, Goo; Cho, Seung‐Sik; Choi, Joon‐Seok; Lee, Sang‐Myeong; Seo, Kang‐Seok; Chae, Jung‐Il; Shim, Jung‐Hyun
• Is Part Of: Phytotherapy research. Volume 34:Number 2(2020)
• Page Start: 388
• Page End: 400
• Publication Date: 2019-11-07
• Subjects: Echinatin -- EGFR -- MET -- Non‐small cell lung cancer -- Apoptosis; Materia medica, Vegetable -- Periodicals; Botany, Medical -- Periodicals; Medicinal plants -- Periodicals; Plant Extracts -- therapeutic use -- Periodicals; Plants, Medicinal -- Periodicals; 581.634
• DOI: 10.1002/ptr.6530
• Languages: English
• ISSNs: 0951-418X

Abstract

Abstract : 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.