title: Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo.
abstract: Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, 510060, China.
authors.forename: Xiao-qin
authors.initials: XQ
authors.lastname: Zhao
authors.forename: Jing-dun
authors.initials: JD
authors.lastname: Xie
authors.forename: Xing-gui
authors.initials: XG
authors.lastname: Chen
authors.forename: Hong May
authors.initials: HM
authors.lastname: Sim
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yong-ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Yueli
authors.initials: Y
authors.lastname: Sun
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Li-wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012235:Rhodamines / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D011804:Quinolines; D012333:RNA, Messenger; D012235:Rhodamines; D004317:Doxorubicin; D051058:Oncogene Protein v-akt; D054460:rho-Associated Kinases; D000251:Adenosine Triphosphatases; C487932:neratinib