Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Picropodophyllotoxin Inhibits Cell Growth and Induces Apoptosis in Gefitinib-Resistant Non-Small Lung Cancer Cells by Dual-Targeting EGFR and MET

  • Jin-Young, Lee (Department of Biological Sciences, Keimyung University) ;
  • Bok Yun, Kang (College of Pharmacy, Chonnam National University) ;
  • Sang-Jin, Jung (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Ah-Won, Kwak (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Seung-On, Lee (Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National University) ;
  • Jin Woo, Park (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Sang Hoon, Joo (College of Pharmacy, Daegu Catholic University) ;
  • Goo, Yoon (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Mee-Hyun, Lee (College of Korean Medicine, Dongshin University) ;
  • Jung-Hyun, Shim (Department of Pharmacy, College of Pharmacy, Mokpo National University)
  • Received : 2022.08.26
  • Accepted : 2022.09.06
  • Published : 2023.03.01
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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

Acknowledgement

This study was funded by the Basic Science Research Program of National Research Foundation Korea (NRF) (No. 2019R1A2C1005899) and an NRF grant funded by the Korea government (MSIT) (No. 2022R1A5A8033794).

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