CHEMOSENSITIZATION AND DRUG ACCUMULATION EFFECTS OF VX-710, VERAPAMIL, CYCLOSPORINE-A, MS-209 AND GF120918 IN MULTIDRUG-RESISTANT HL60 ADR CELLS EXPRESSING THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN MRP/

Overexpression of the multidrug resistance MDR1 gene product P-glycopr otein and/or the multidrug resistance-associated protein MRP confers m ultidrug resistance to cancer cells. The pipecolinate derivative VX-71 0 has previously been demonstrated to reverse MDR1-mediated multidrug resistance at concentrations of 0.5-2.5 mu M by direct interaction wit h P-glycoprotein and inhibition of its drug efflux activity. In this s tudy we investigated whether VX-710 as well as four other known MDR1 m odulators could also reverse multidrug resistance mediated by MRP. VX- 710 at 0.5-5 mu M restored senstivity of MRP-expressing HL60/ADR promy elocytic leukemia cells to the cytotoxic action of doxorubicin, etopos ide and vincristine. VX-710 was approximately 2-fold more effective th an verapamil, MS-209 and CsA in modulating MRP-mediated multidrug resi stance, whereas GF120918 had no significant effect. VX-710 was also mo re effective than verapamil, MS-209 and CsA in restoring the daunorubi cin accumulation deficit in HL60/ADR cells and in increasing calcein u ptake. A photoaffinity analog of VX-710, [H-3]VF-13,159, specifically photo labeled the MRP protein and unlabeled VX-710 inhibited this bind ing in a concentration-dependent manner. These data suggest that VX-71 0 is not only a potent modulator of P-glycoprotein-mediated multidrug resistance, but also affects multidrug resistance in MRP-expressing ce lls and may exert its action, at least in part, by binding directly to MRP.