title: Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP.
abstract: Overexpression of the multidrug resistance MDR1 gene product P-glycoprotein and/or the multidrug resistance-associated protein MRP confers multidrug resistance to cancer cells. The pipecolinate derivative VX-710 has previously been demonstrated to reverse MDR1-mediated multidrug resistance at concentrations of 0.5-2.5 microM by direct interaction with P-glycoprotein and inhibition of its drug efflux activity. In this study we investigated whether VX-710 as well as four other known MDR1 modulators could also reverse multidrug resistance mediated by MRP. VX-710 at 0.5-5 microM restored senstivity of MRP-expressing HL60/ADR promyelocytic leukemia cells to the cytotoxic action of doxorubicin, etoposide and vincristine. VX-710 was approximately 2-fold more effective than verapamil, MS-209 and CsA in modulating MRP-mediated multidrug resistance, whereas GF120918 had no significant effect. VX-710 was also more effective than verapamil, MS-209 and CsA in restoring the daunorubicin accumulation deficit in HL60/ADR cells and in increasing calcein uptake. A photoaffinity analog of VX-710, [3H]VF-13,159, specifically photo labeled the MRP protein and unlabeled VX-710 inhibited this binding in a concentration-dependent manner. These data suggest that VX-710 is not only a potent modulator of P-glycoprotein-mediated multidrug resistance, but also affects multidrug resistance in MRP-expressing cells and may exert its action, at least in part, by binding directly to MRP.
authors.affiliation: Vertex Pharmaceuticals Inc., Cambridge, MA 02139-4242, USA.
authors.forename: U A
authors.initials: UA
authors.lastname: Germann
authors.forename: P J
authors.initials: PJ
authors.lastname: Ford
authors.forename: D
authors.initials: D
authors.lastname: Shlyakhter
authors.forename: V S
authors.initials: VS
authors.lastname: Mason
authors.forename: M W
authors.initials: MW
authors.lastname: Harding
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000345:Affinity Labels; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000494:pharmacology; D005452:Fluoresceins / Q000493:pharmacokinetics; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000345:Affinity Labels; D000970:Antineoplastic Agents; D016572:Cyclosporine; D003630:Daunorubicin; D004317:Doxorubicin; D005047:Etoposide; D005452:Fluoresceins; D007546:Isoquinolines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010880:Piperidines; D011725:Pyridines; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D014316:Tritium; D014700:Verapamil; D014750:Vincristine; C106078:VF 13,159; C087719:dofequidar; C106077:biricodar; C083501:Elacridar; C007740:fluorexon