title: Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo.
abstract: Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2- overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Wang
authors.affiliation: School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, P.R. China.
authors.forename: Kenneth Kin Wah
authors.initials: KK
authors.lastname: To
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Huang
authors.affiliation: First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jing-Hong
authors.initials: JH
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Zhen-Cong
authors.initials: ZC
authors.lastname: Huang
authors.affiliation: First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D019772:Topotecan / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D011799:Quinazolines; D000077716:Afatinib; D019772:Topotecan