Gefitinib reverses chemotherapy resistance in gefitinib-insensitive multidrug resistant cancer cells expressing ATP-binding cassette family protein
Journal
Cancer Research
Journal Volume
65
Journal Issue
15
Pages
6943-6949
Date Issued
2005
Author(s)
Abstract
Gefitinib inhibits the ATP-binding site of the tyrosine kinase associated with the epidermal growth factor receptor. It is conceivable that gefitinib may inhibit functions of ATP-binding cassette (ABC) transporters by binding at their ATP-binding sites. The aim of this study is to systematically explore the combined effect of gefitinib and chemotherapeutic agents in gefitinib- insensitive multidrug resistant (MDR) cells that overexpress ABC transporters. MCF7 breast carcinoma cells and CLI lung adenocarcinoma cells were both insensitive to gefitinib. MDR cancer cells were developed by stepwise escalating concentrations of each chemotherapeutic agent in culture media. Cells that overexpress P-glycoprotein (MCF7/Adr and CLI/Pac), breast cancer-resistant protein (MCF7/TPT and CLI/Tpt), and MDR-associated protein 1 (MCF7/Vp) were used in this study. All resistant mutants were insensitive to gefitinib. Gefitinib (0.3-3 μmol/L) added to culture media had no effect on IC50 values of paclitaxel, topotecan, doxorubicin, or etoposide in wild-type MCF7 or CLI cells. In contrast, these concentrations of gefitinib caused a dose-dependent reversal of resistance to paclitaxel in CLI/Pac cells, to doxorubicin in MCF7/ADR cells, and to topotecan in CLI/Tpt and MCF7/TPT cells. Gefitinib had no influence on sensitivity to etoposide in MDR-associated protein1 overexpressing MCF7/VP cells. Topotecan efflux was inhibited and accumulation was partially restored in CLI/Tpt and MCF7/TPT cells when cells were incubated simultaneously with gefitinib. Our results suggest that the interaction of gefitinib and chemotherapeutic agents does occur in cells expressing one of these two proteins. ? 2005 American Association for Cancer Research.
SDGs
Other Subjects
ABC transporter; epidermal growth factor receptor; etoposide; gefitinib; glycoprotein P; sulforhodamine B; topotecan; antineoplastic activity; article; breast carcinoma; cancer cell; cancer chemotherapy; cancer resistance; cell strain MCF 7; concentration response; drug accumulation; drug cytotoxicity; drug uptake; flow cytometry; gene mutation; gene overexpression; human; human cell; IC 50; lung adenocarcinoma; multidrug resistance; priority journal; protein expression; protein family; wild type; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Etoposide; Humans; Lung Neoplasms; Paclitaxel; Protein Kinase Inhibitors; Quinazolines; Topotecan
Type
journal article