Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer

  • Kim, Han Sol (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Oh, Ha-Na (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Kwak, Ah-Won (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Kim, Eunae (College of Pharmacy, Chosun University) ;
  • Lee, Mee-Hyun (College of Korean Medicine, Dongshin University) ;
  • Seo, Ji-Hye (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University) ;
  • Cho, Seung-Sik (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Yoon, Goo (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Chae, Jung-Il (Department of Dental Pharmacology, School of Dentistry, Jeonbuk National University) ;
  • Shim, Jung-Hyun (Department of Pharmacy, College of Pharmacy, Mokpo National University)
  • Received : 2021.01.25
  • Accepted : 2021.03.02
  • Published : 2021.04.28
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Abstract

As one of the major types of lung cancer, non-small cell lung cancer (NSCLC) accounts for the majority of cancer-related deaths worldwide. Treatments for NSCLC includes surgery, chemotherapy, and targeted therapy. Among the targeted therapies, resistance to inhibitors of the epidermal growth factor receptor (EGFR) is common and remains a problem to be solved. MET (hepatocyte growth factor receptor) amplification is one of the major causes of EGFR-tyrosine kinase inhibitor (TKI) resistance. Therefore, there exists a need to find new and more efficacious therapies. Deoxypodophyllotoxin (DPT) extracted from Anthriscus sylvestris roots exhibits various pharmacological activities including anti-inflammation and anti-cancer effects. In this study we sought to determine the anti-cancer effects of DPT on HCC827GR cells, which are resistant to gefitinib (EGFR-TKI) due to regulation of EGFR and MET and their related signaling pathways. To identify the direct binding of DPT to EGFR and MET, we performed pull-down, ATP-binding, and kinase assays. DPT exhibited competitive binding with ATP against the network kinases EGFR and MET and reduced their activities. Also, DPT suppressed the expression of p-EGFR and p-MET as well as their downstreat proteins p-ErbB3, p-AKT, and p-ERK. The treatment of HCC827GR cells with DPT induced high ROS generation that led to endoplasmic-reticulum stress. Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results demonstrate the apoptotic effects of DPT on HCC827GR cells and signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.

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References

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