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Modulation of P‐glycoprotein but not MRP1‐ or BCRP‐mediated drug resistance by LY335979
Author(s) -
Shepard Robert L.,
Cao Jin,
Starling James J.,
Dantzig Anne H.
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10792
Subject(s) - mitoxantrone , abcg2 , p glycoprotein , pharmacology , multidrug resistance associated protein 2 , multiple drug resistance , drug resistance , atp binding cassette transporter , hl60 , vinorelbine , biology , chemistry , in vitro , transporter , biochemistry , chemotherapy , cisplatin , genetics , gene , microbiology and biotechnology
Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P‐glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp‐mediated resistance can be modulated by coadministration with the highly potent, selective inhibitor, LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3‐day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF‐7 breast cancer transfectants. LY335979, at 0.5 μM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp‐expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1‐expressing HL60/ADR or drug‐sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP‐mediated drug resistance, the sensitivity of 26‐fold mitoxantrone resistant, BCRP‐transfected MCF‐7 cells was evaluated. Addition of 5 μM LY335979, a concentration ∼100‐fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [ 125 I]Iodomycin photolabeled Pgp in CEM/VLB 100 membranes and was inhibited by 5 μM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF‐7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1‐ or BCRP‐mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells. © 2002 Wiley‐Liss, Inc.