Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.113
Picropodophyllotoxin Inhibits Cell Growth and Induces Apoptosis in Gefitinib-Resistant Non-Small Lung Cancer Cells by Dual-Targeting EGFR and MET
Jin-Young Lee1,†, Bok Yun Kang2,†, Sang-Jin Jung3, Ah-Won Kwak3, Seung-On Lee4, Jin Woo Park3,4, Sang Hoon Joo5, Goo Yoon3, Mee-Hyun Lee6,* and Jung-Hyun Shim3,4,7,*
1Department of Biological Sciences, Keimyung University, Daegu 42601,
2College of Pharmacy, Chonnam National University, Gwangju 61186,
3Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554,
4Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University, Muan 58554,
5College of Pharmacy, Daegu Catholic University, Gyeongsan 38430,
6College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea
7The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan 450008, China
*E-mail: s1004jh@gmail.com (Shim JH), mhyun_lee@hanmail.net (Lee MH)
Tel: +82-61-450-2684 (Shim JH), +82-61-330-3516 (Lee MH)
Fax: +82-61-450-2689 (Shim JH), +82-61-330-3519 (Lee MH)
The first two authors contributed equally to this work.
Received: August 26, 2022; Revised: September 5, 2022; Accepted: September 6, 2022; Published online: October 25, 2022.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resistance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunction, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.
Keywords: Picropodophyllotoxin (PPT), EGFR, MET, Non-small cell lung cancer, Apoptosis


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