title: Linsitinib (OSI-906) antagonizes ATP-binding cassette subfamily G member 2 and subfamily C member 10-mediated drug resistance.
abstract: In this study we investigated the effect of linsitinib on the reversal of multidrug resistance (MDR) mediated by the overexpression of the ATP-binding cassette (ABC) subfamily members ABCB1, ABCG2, ABCC1 and ABCC10. Our results indicate for the first time that linsitinib significantly potentiate the effect of anti-neoplastic drugs mitoxantrone (MX) and SN-38 in ABCG2-overexpressing cells; paclitaxel, docetaxel and vinblastine in ABCC10-overexpressing cells. Linsitinib moderately enhanced the cytotoxicity of vincristine in cell lines overexpressing ABCB1, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, linsitinib significantly increased the intracellular accumulation and decreased the efflux of [(3)H]-MX in ABCG2-overexpressing cells and [(3)H]-paclitaxel in ABCC10-overexpressing cells. However, linsitinib, at a concentration that reversed MDR, did not significantly alter the expression levels of either the ABCG2 or ABCC10 transporter proteins. Furthermore, linsitinib did not significantly alter the intracellular localization of ABCG2 or ABCC10. Moreover, linsitinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner. Overall, our study suggests that linsitinib attenuates ABCG2- and ABCC10-mediated MDR by directly inhibiting their function as opposed to altering ABCG2 or ABCC10 protein expression.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.affiliation: Department of Pharmaceutical Sciences, 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: Department of Pharmaceutical Sciences, 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: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, MD 20892, USA.
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, MD 20892, USA.
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.affiliation: Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Electronic address: fulw@mail.sysu.edu.cn.
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.affiliation: Department of Pharmaceutical Sciences, 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; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008942:Mitoxantrone / Q000493:pharmacokinetics; D008958:Models, Molecular; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007093:Imidazoles; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C421142:ABCC10 protein, human; C116614:ABCG2 protein, human
keywords: ABCC10; ABCG2; Linsitinib; Multi-drug resistance; Tyrosine kinase inhibitor
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