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

Abstract

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.

• Authors: Tsuyoshi Ohta, Masahide Ohmichi, Tae Shibuya, Toshifumi Takahashi, Seiji Tsutsumi, Kazuhiro Takahashi, Hirohisa Kurachi
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 13 Issue 6 Pg. 408-16 (Apr 2012) ISSN: 1555-8576 [Electronic] United States
• PMID: 22313686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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