title: Erlotinib (Tarceva, OSI-774) antagonizes ATP-binding cassette subfamily B member 1 and ATP-binding cassette subfamily G member 2-mediated drug resistance.
abstract: It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)- and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)-mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1- or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E(2)17 beta G and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1- and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York 11439, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Xing-Xiang
authors.initials: XX
authors.lastname: Peng
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.forename: Qiu-Sheng
authors.initials: QS
authors.lastname: Si
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; 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*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride; D004958:Estradiol / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D004958:Estradiol; D008942:Mitoxantrone; D000069347:Erlotinib Hydrochloride; D017239:Paclitaxel; D000077156:Gefitinib; D008727:Methotrexate