High-throughput screening for daunorubicin-mediated drug resistance identifies mometasone furoate as a novel ABCB1-reversal agent.
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.
Winter
Stuart S
SS
Pediatric Hematology-Oncology, MSC 105590, University of New Mexico, Albuquerque, NM 87131-5311, USA. swinter@salud.unm.edu
Lovato
Debbie M
DM
Khawaja
Hadya M
HM
Edwards
Bruce S
BS
Steele
Irena D
ID
Young
Susan M
SM
Oprea
Tudor I
TI
Sklar
Larry A
LA
Larson
Richard S
RS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001681:Biological Assay; D002232:Carbocyanines / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D000068656:Mometasone Furoate; D011244:Pregnadienediols / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002232:Carbocyanines; D011244:Pregnadienediols; D000068656:Mometasone Furoate; D003630:Daunorubicin