Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia

Abstract

Significantly decreased uptake and retention of daunorubicin (DAU) and Adriamycin (ADR) have been reported in sublines of P388 leukemia resistant to these anthracyclines. We studied the effects of inhibitors of oxidative phosphorylation on uptake and retention of DAU and ADR in order to characterize the transport process for these anthracyclines and to clarify further the alteration in resistant cells. In glucose-free medium, uptake of DAU and ADR was accelerated by metabolic inhibitors to a greater extent in resistant cells than in sensitive cells. Under these conditions, drug uptake was similar in sensitive and resistant cells. When glucose was added to the incubation medium in the presence of 2,4-dinitrophenol, efflux of DAU from both sensitive and resistant cells was observed. Net efflux of ADR was also observed with the resistant cells, whereas glucose markedly inhibited 2,4-dinitrophenol-stimulated uptake of ADR by the sensitive cells. Furthermore, in sensitive and resistant cells preloaded with ADR and DAU, efflux of the drugs was inhibited by the addition of 2,4-dinitrophenol. These results suggest that there is an active outward transport mechanism for anthracyclines in P388 leukemia cells and that enhanced activity of this efflux process renders cells highly resistant to the cytostatic and cytotoxic effects of ADR and DAU.