Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) inhibit the function of certain adenosine triphosphate (ATP)-binding cassette transporters, including P-glycoprotein/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2. We previously reported an antagonistic activity of gefitinib towards BCRP. We have now analyzed the effects of erlotinib, another EGFR-TKI, on P-glycoprotein and BCRP. As with gefitinib, erlotinib effectively reversed BCRP-mediated resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and mitoxantrone. In contrast, we found that erlotinib effectively suppressed P-glycoprotein-mediated resistance to vincristine and paclitaxel, but did not suppress resistance to mitoxantrone and doxorubicin. Conversely, erlotinib appeared to enhance P-glycoprotein-mediated resistance to mitoxantrone in K562/MDR cells. This bidirectional activity of erlotinib was not observed with verapamil, a typical P-glycoprotein inhibitor. Flow cytometric analysis showed that erlotinib co-treatment restored intracellular accumulation of mitoxantrone in K562 cells expressing BCRP, but not in cells expressing P-glycoprotein. Consistently, erlotinib did not inhibit mitoxantrone efflux in K562/MDR cells although it did vincristine efflux in K562/MDR cells and mitoxantrone efflux in K562/BCRP cells. Intravesicular transport assay showed that erlotinib inhibited both P-glycoprotein-mediated vincristine transport and BCRP-mediated estrone 3-sulfate transport. Intriguingly, Lineweaver-Burk plot suggested that the inhibitory mode of erlotinib was a mixed type for P-glycoprotein-mediated vincristine transport whereas it was a competitive type for BCRP-mediated estrone 3-sulfate transport. Collectively, these observations indicate that the pharmacological activity of erlotinib on P-glycoprotein-mediated drug resistance is dependent upon the transporter substrate. These findings will be useful in understanding the pharmacological interactions of erlotinib used in combinational chemotherapy.
Noguchi
Kohji
K
Division of Chemotherapy, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo, Japan.
Kawahara
Haruka
H
Kaji
Airi
A
Katayama
Kazuhiro
K
Mitsuhashi
Junko
J
Sugimoto
Yoshikazu
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D020014:K562 Cells; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014750:Vincristine; D004317:Doxorubicin; D008942:Mitoxantrone; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017239:Paclitaxel