Gefitinib (ZD1839) increases the efficacy of cisplatin in ovarian cancer cells

Cancer Biol Ther. 2012 Apr;13(6):408-16. doi: 10.4161/cbt.19292. Epub 2012 Apr 1.


We examined the effect of gefitinib (ZD1839), a selective epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, on cytotoxicity to cisplatin, EGFR downstream signaling, apoptosis and the association between the inhibition of DNA repair by gefitinib and the expression of DNA-dependent protein kinase (DNA-PK) using three ovarian cancer cell lines. In the presence of gefitinib, cisplatin-induced growth inhibition and apoptosis were significantly enhanced in Caov-3 and RMG-1 cells, which express EGFR, and in A2780, which lacks EGFR but expresses HER-2. Gefitinib significantly inhibited the cisplatin-induced ERK and Akt activation in Caov-3 and RMG-1 cells but not in A2780 cells. In all three cell lines, there was delayed repair of DNA intrastrand cross-links damaged by cisplatin used in combination with gefitinib, compared with cisplatin alone. The reduction in DNA-PK levels persisted when cells were exposed to combinations of cisplatin and gefitinib in all cell lines. Moreover, the delayed repair was cancelled by anti-HER2 small-interfering RNA transfection in A2780 cells. These results suggest that combination therapy with cisplatin and gefitinib may increase the therapeutic efficacy of cisplatin by blocking EGFR downstream signaling and/or inhibiting DNA repair in ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology*
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • DNA-Activated Protein Kinase / metabolism
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gefitinib
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology*
  • Receptor, ErbB-2 / genetics
  • Signal Transduction


  • Quinazolines
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • DNA-Activated Protein Kinase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Cisplatin
  • Gefitinib