Gefitinib (ZD1839) increases the efficacy of cisplatin in ovarian cancer cells.
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.
Department of Obstetrics and Gynecology, Yamagata University, School of Medicine, Yamagata, Japan. oota-t@med.id.yamagata-u.ac.jp
Tsuyoshi
T
Ohta
Masahide
M
Ohmichi
Tae
T
Shibuya
Toshifumi
T
Takahashi
Seiji
S
Tsutsumi
Kazuhiro
K
Takahashi
Hirohisa
H
Kurachi
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction
D002945:Cisplatin; D051747:DNA-Activated Protein Kinase; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human