Deoxypodophyllotoxin Inhibits Cell Growth and Induces Apoptosis by Blocking EGFR and MET in Gefitinib-Resistant Non-Small Cell Lung Cancer

J Microbiol Biotechnol. 2021 Apr 28;31(4):559-569. doi: 10.4014/jmb.2101.01029.

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.

Keywords: Deoxypodophyllotoxin; apoptosis; gefitinib-resistant; lung cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apiaceae / chemistry
  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Drugs, Chinese Herbal / pharmacology*
  • ErbB Receptors / antagonists & inhibitors
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology*
  • Membrane Potential, Mitochondrial / drug effects
  • Podophyllotoxin / analogs & derivatives*
  • Podophyllotoxin / pharmacology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Drugs, Chinese Herbal
  • deoxypodophyllotoxin
  • EGFR protein, human
  • ErbB Receptors
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Podophyllotoxin
  • Gefitinib