title: Selective reversal of BCRP-mediated MDR by VEGFR-2 inhibitor ZM323881.
abstract: The expression of breast cancer resistant protein (BCRP) in lung cancer is correlated with development of multidrug resistance (MDR) and therefore leads to lower response to chemotherapy. ZM323881, a previously developed selective VEGFR-2 inhibitor, was found to have inhibitory effects on BCRP-mediated MDR in this investigation. ZM323881 significantly decreased the cytotoxic doses of mitoxantrone and SN-38 in BCRP-overexpressing NCI-H460/MX20 cells. Mechanistic studies revealed that ZM323881 effected by inhibiting BCRP-mediated drug efflux, leading to intracellular accumulation of BCRP substrates. No significant alteration in the expression levels and localization pattern of BCRP was observed when BCRP-overexpressing cells were exposed to ZM323881. Stimulated bell-shaped ATPase activities were observed. Molecular docking suggested that ZM323881 binds to the modulator site of BCRP and the binding pose is stable validated by 100ns molecular dynamic simulation. Overall, our results indicated that ZM323881 reversed BCRP-related MDR by inhibiting its efflux function. These findings might be useful in developing combination chemotherapy for MDR cancer treatment.
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Yun-Kai
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Zhang
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: College of Liberal Arts and Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.affiliation: College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address: chenz@stjohns.edu.
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000502:physiology*; D001562:Benzimidazoles / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D011799:Quinazolines; C478783:ZM323881; D004317:Doxorubicin; D008942:Mitoxantrone; D040301:Vascular Endothelial Growth Factor Receptor-2; C017807:bisbenzimide ethoxide trihydrochloride
keywords: BCRP; Lung cancer; Multidrug resistance; ZM323881