title: The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance.
abstract: ABCG2 is an important member of ATP-binding cassette (ABC) transporter shown to confer drug resistance in cancer cells. Recent studies show that an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, is able to modulate the function of ABCG2 and reverse ABCG2-mediated multidrug resistance (MDR) in cancer cells. Additionally, ABCG2 expression has been shown to impact treatment efficacy and development of side-effects in patients receiving gefitinib. However, it is unclear whether other EGFR TKIs interact with ABCG2 in a similar manner. In the present study, we investigated the interaction of two other EGFR TKIs, AG1478 and erlotinib, with ABCG2. Our data show that AG1478 and erlotinib potently sensitized drug-resistant cells overexpressing either wild-type or mutated ABCG2 to the ABCG2 substrate anti-cancer drugs flavopiridol and mitoxantrone. Neither AG1478 nor erlotinib sensitized ABCG2-overexpressing cells to drugs that are not substrates of ABCG2 nor did they impact drug sensitivity of parental cells. Furthermore, AG1478 and erlotinib were able to significantly enhance the intracellular accumulation of mitoxantrone in cells expressing either wild-type or mutated ABCG2. Additionally, they did not alter the protein expression of ABCG2 in the ABCG2-overexpressing cells. Taken together, we conclude that AG1478 and erlotinib potently reverse ABCG2-mediated MDR through directly inhibiting the drug efflux function of ABCG2 in the ABCG2-overexpressing cells. These results will be useful in the development of novel and more effective EGFR TKIs as well as the development of combinational chemotherapeutic strategies.
authors.affiliation: Department of Pharmaceutical Sciences, St. John's University, Jamaica, NY 11439, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Smitaben
authors.initials: S
authors.lastname: Parmar
authors.forename: Xing-Xiang
authors.initials: XX
authors.lastname: Peng
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Yining
authors.initials: Y
authors.lastname: Shao
authors.forename: Yang-Min
authors.initials: YM
authors.lastname: Chen
authors.forename: Feiyang
authors.initials: F
authors.lastname: Zang
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D008942:Mitoxantrone; D000069347:Erlotinib Hydrochloride