THE SPECIFIC BISINDOLYLMALEIMIDE PKC-INHIBITOR GF 109203X EFFICIENTLYMODULATES MRP-ASSOCIATED MULTIPLE-DRUG RESISTANCE

The newly identified drug transporter MRP is functionally linked to a multiple drug resistance independent from P-glycoprotein. Resistance m odifiers for this type of MDR are rare at present. We analyzed the mod ulating effect of the highly selective bisindolylmaleimide PKC inhibit or GF 109203X on the MRP overexpressing human MDR sublines HL60/AR and GLC4/ADR. Applying a 72 hour MTT-assay we demonstrate a complete reve rsal of the vincristine resistance of HL60/AR cells. Adriamycin resist ance of HL60/AR, or vincristine resistance of GLC4/ADR were partially reversed. Furthermore, rhodamine 123 efflux from HL60/AR was strongly modulated by GF 109203X. Since the PKC inhibitor did not significantly influence MRP gene expression at the mRNA level which was examined by cDNA-PCR, our results suggest either a direct interaction of the comp ound with MRP or/and an indirect influence on MRP activity via alterin g the phosphorylation status of the transporter. (C) 1995 Academic Pre ss, Inc.