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.

Links

Publisher Full Text

Authors

Sun YL, Kathawala RJ, Singh S, Zheng K, Talele TT, Jiang WQ, Chen ZS

Institution

Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professionals, St John's University, Queens, New York, USA.

Source

Anti-cancer drugs 23:8 2012 Sep pg 865-73

MeSH

ATP-Binding Cassette Transporters
Antineoplastic Agents
Blotting, Western
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Leukotriene Antagonists
Models, Molecular
Neoplasm Proteins
Neoplasms
P-Glycoprotein
Tosyl Compounds

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22614107