Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of daunorubicin and doxorubicin in HL60 and its resistant cells and comparison with those of pirarubicin.

Abstract

We examined the transport mechanisms of daunorubicin (DNR) and doxorubicin (ADR) in HL60 and HL60/THP cells which were the non-P-glycoprotein-mediated resistant clone of the parent HL60 cells and showed a low degree of resistance, and compared them with those of pirarubicin (THP). In both lines, it appeared that the uptakes of DNR and ADR were time-, temperature- and concentration-dependent and energy independent, and the transport of DNR consisted of saturable and nonsaturable components. They were pumped out from the cells time-, temperature- and energy-dependently. There were no differences in the accumulation amount of either DNR or ADR between HL60 and HL60/THP cells. Comparing the transport of DNR or ADR with that of THP, the uptake amounts of DNR and THP were approximately equal, and were greater than that of ADR in both types of cell. In cis-inhibition experiments, DNR inhibited the THP uptake noncompetitively in the parent and resistant cells, in contradiction of the previously reported result in which ADR showed competitive inhibition (Nagasawa, K. et al., Cancer Chemother. Pharmacol., in press). The THP accumulation appeared to be increased by preload of DNR and ADR, indicating a counter transport. Thus, DNR and ADR as well as THP might be incorporated via a common carrier-mediated transport system, but DNR uptake in part appeared to follow a nonsaturable transport, and its binding site in the carrier might differ from that of THP and ADR in both HL60 and HL60/THP cells.