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Journal of Biomolecular Screening
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High-Throughput Screening for Daunorubicin-Mediated Drug Resistance Identifies Mometasone Furoate as a Novel ABCB1-Reversal Agent

Stuart S. Winter

University of New Mexico Health Sciences Center, Departments of Pediatrics, swinter{at}salud.unm.edu

Debbie M. Lovato

University of New Mexico Health Sciences Center, Department of Pathology

Hadya M. Khawaja

University of New Mexico Health Sciences Center, Department of Pathology

Bruce S. Edwards

University of New Mexico Health Sciences Center, Department of Pathology, University of New Mexico Health Sciences Center, Flow Cytometry Resource

Irena D. Steele

University of New Mexico Health Sciences Center, Flow Cytometry Resource

Susan M. Young

University of New Mexico Health Sciences Center, Flow Cytometry Resource

Tudor I. Oprea

University of New Mexico Health Sciences Center, Division of Bio-computing, Albuquerque, New Mexico

Larry A. Sklar

University of New Mexico Health Sciences Center, Department of Pathology, University of New Mexico Health Sciences Center, Flow Cytometry Resource

Richard S. Larson

University of New Mexico Health Sciences Center, Department of Pathology

The overexpression of P-glycoprotein, encoded by the ATP Binding Cassette B1 (ABCB1) gene, contributes to multidrug resistance (MDR) and is considered one of the major obstacles to successful cancer chemotherapy. The authors previously developed a T-lineage acute lymphoblastic leukemia (T-ALL) cell line that overexpresses ABCB1 and exhibits MDR to daunorubicin (DNR), prednisolone, and vincristine. Using this cell line and the fluorescent probe JC-1, they developed a flow cytometry-based, high-throughput screening (HTS) assay that quantifies ABCB1 efflux. They screened a library of 880 off-patent drugs for their ability to inhibit ABCB1 efflux and then measured the ability of 11 lead compounds to reverse in vitro DNR-mediated drug resistance and the toxic doses for each agent. Seven of the 11 drugs were able to reverse drug resistance at a concentration significantly below its toxic dose. Of the remaining 7, only 1 compound, mometasone furoate, has not been previously described as an ABCB1 antagonist to DNR-mediated drug resistance. On the basis of its high ABC modulator activity and relatively large in vitro therapeutic window, this drug warrants further investigation. In addition, the approach used in this study is useful for identifying off-patent drugs that may be repurposed for novel clinical indications. (Journal of Biomolecular Screening 2008:185-193)

Key Words: high-throughput screening • T-ALL • transporter-related multidrug resistance • ABCB1 • Prestwick Chemical Library

This version was published on March 1, 2008

Journal of Biomolecular Screening, Vol. 13, No. 3, 185-193 (2008)
DOI: 10.1177/1087057108314610
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