title: Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells.
abstract: Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki 852-8501, Japan. tkita@ma.ejnet.ne.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kitazaki
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Seiji
authors.initials: S
authors.lastname: Doi
authors.forename: Masa
authors.initials: M
authors.lastname: Yasunaga
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takemura
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yabuuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soda
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D015151:Immunoblotting; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015233:Models, Statistical; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011799:Quinazolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D020112:Rhodamine 123; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D000251:Adenosine Triphosphatases; C022616:thiazolyl blue; D000077156:Gefitinib