title: GSK1904529A, a Potent IGF-IR Inhibitor, Reverses MRP1-Mediated Multidrug Resistance.
abstract: Overexpression of multidrug-resistant efflux transporters is one of the major causes of chemotherapy failure. MRP1, a 190 kDa efflux transporter, confers resistance to a wide of range of chemotherapeutic drugs. Here we study the cellular effects of GSK1904529A in reversing MRP1-mediated drug resistance. Cytotoxicity of GSK1904529A was determined by MTT assay. Reversal effects of GSK1904529A in combination with MRP1 substrates were determined. The intracellular accumulation and efflux of MRP1 substrate was measured by scintillation counter and protein expression was determined by Western blotting analysis. Cell cycle effects of GSK1904529A in combination with MRP1 substrates were determined by flow cytometric analysis. GSK1904529A, at non-toxic concentrations, enhanced the cytotoxicity of MRP1 substrates in HEK293/MRP1 cells. Furthermore, GSK1904529A increased the intracellular accumulation of [3H]-vinblastine by inhibiting the efflux function of MRP1. GSK1904529A did not alter the expression level of MRP1, induced a G0/G1 phase cell cycle arrest. Our results indicated that GSK1904529A significantly increased the sensitivity of MRP1 overexpressing cells to chemotherapeutic agents. Furthermore, GSK1904529A enhanced the efficacy of chemotherapeutic drugs that are substrates of MRP1. J. Cell. Biochem. 118: 3260-3267, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Pranav
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.|Medicine Experiment Center, Weifang Medical University, Weifang Shandong Province, 261053, People's Republic of China.
authors.forename: Meina
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Silpa
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: College of Animal Science, South China Agricultural University, Guangzhou, Guangdong Province, 510642, People's Republic of China.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Timothy
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Ziyue
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, 11439.
authors.forename: Zhe-Sheng
authors.identifier: 0000-0002-8289-097X
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D002461:Cell Line, Transformed; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects* / Q000235:genetics
chemical_list: D007093:Imidazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011725:Pyridines; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C000607695:GSK1904529A; C000597236:IGF1R protein, human; C421109:multidrug resistance-associated protein 1
keywords: ABC TRANSPORTERS; GSK1904529A; MRP1; MULTIDRUG-RESISTANCE