title: Zafirlukast antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance.
abstract: ATP-binding cassette (ABC) transporters are present in the majority of human tumors and are involved in multidrug resistance (MDR). Therefore, compounds that inhibit the function of ABC transporters may improve the efficacy of anticancer agents. Previous research has shown that zafirlukast is a reversal drug for multidrug resistance protein (MRP) 1-mediated MDR. In the present study, we assessed whether zafirlukast could be a reversal agent for other ABC transporter-mediated MDR. Using the MTT assay, we found that zafirlukast enhanced the cytotoxicity of several anticancer drugs that are substrates of breast cancer resistance proteins (BCRP/ABCG2), including mitoxantrone and SN-38. Furthermore, zafirlukast could partially reverse P-glycoprotein-mediated (P-gp/ABCB1) and MRP7 (ABCC10)-mediated MDR at nontoxic doses. Studies on [(3)H]-mitoxantrone accumulation and efflux have shown that zafirlukast increases the intracellular accumulation of [(3)H]-mitoxantrone by directly inhibiting ABCG2-mediated drug efflux. Western blot analysis indicated that zafirlukast did not alter the expression of ABCG2. In addition, a docking model predicted the binding conformation of zafirlukast within the transmembrane region of homology-modeled human ABCG2. Our findings suggest a possible strategy to potentially enhance the activity of anticancer drugs using a clinically approved drug with known side effects and drug-drug interactions.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professionals, St John's University, Queens, New York, USA.
authors.forename: Yue-Li
authors.initials: YL
authors.lastname: Sun
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.forename: Satyakam
authors.initials: S
authors.lastname: Singh
authors.forename: Kelvin
authors.initials: K
authors.lastname: Zheng
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Jiang
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles; D020024:Leukotriene Antagonists / Q000494:pharmacology; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D020024:Leukotriene Antagonists; D009363:Neoplasm Proteins; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; C062735:zafirlukast