Inhibition of multidrug resistance-associated protein (MRP) activity by rifampicin in human multidrug-resistant lung tumor cells

The multidrug resistance-associated protein (MRP) is a drug efflux membrane pump conferring multidrug resistance on tumor cells. In order to look for compounds that can lead to reversal of such a resistance, the antituberculo sis compound rifampicin, belonging to the chemical class of rifamycins, was examined for its effect on MRP activity in human multidrug resistant lung cancer GLC4/ADR cells. Rifampicin was shown to increase accumulation of the MRP substrate calcein in GLC4/ADR cells in a dose-dependent manner by inhi biting its MRP-mediated efflux from the cells; it also enhanced intracellul ar retention of another substrate of MRP such as the anticancer drug vincri stine in the resistant cells. By contrast, the antituberculosis drug did no t alter cellular levels of accumulation of either calcein or vincristine in parental drug-sensitive GLC4 cells. Other rifamycins such as rifamycin B a nd rifamycin SV were also demonstrated to increase intracellular accumulati on of calcein in GLC4/ADR cells. These results therefore indicate that rifa mycins, including rifampicin, probably constitute a new chemical class of m odulators down-regulating MRP-mediated drug transport. (C) 1999 Elsevier Sc ience Ireland Ltd. All rights reserved.