biricodar and dofequidar

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.

Topics: Acridines; Affinity Labels; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Cyclosporine; Daunorubicin; Doxorubicin; Drug Resistance, Multiple; Etoposide; Fluoresceins; HL-60 Cells; Humans; Isoquinolines; Multidrug Resistance-Associated Proteins; Piperidines; Pyridines; Quinolines; Tetrahydroisoquinolines; Tritium; Verapamil; Vincristine