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Acquisition of Resistance to Cisplatin Is Accompanied by Changes in the Cellular Pharmacology of Copper^{1 ,2}

Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093-0058 [K. K., A. K., R. S., A. H., G. S., M. M., S. B. H.]; Skyepharma, Inc., San Diego, California 92121 [M. R.]; and University of California, San Francisco, San Francisco, California 94143 [Y-M. K.]

Impaired uptake of cisplatin (DDP) consistently accompanies the acquisitionof resistance to the platinum drugs. The pathways by which DDP entersor exits from cells remain poorly defined. Using three pairs of human ovarian carcinoma cell lines, each consisting of a sensitive parental line and a stably DDP-resistant subline derived by in vitro selection, resistance to DDP was found to be accompanied by cross-resistance to Cu. Accumulation of DDP in the resistant sublines ranged from 38 to 67% of that in the parental line at 1 h, and DNA adduct formation varied from 10 to 38% of that in the sensitive cells. The DDP-resistant cells had 22–56% lower basal levels of copper, and the copper levels were only 27–46% of those observed in the sensitive parental lines after a 24-h exposure to medium supplemented with copper. The initial influx rate for DDP in the three resistant cell lines ranged from 23 to 55% of that in the sensitive cells of each pair; the initial influx rate for copper in the resistant cells varied from 56 to 75% of control. Studies performed using one pair of cell lines demonstrated that for both copper and DDP the initial efflux rate was lower, whereas the terminal efflux rate was higher in the resistant cells. On Western blot analysis all three resistant lines exhibited increased expression of one or the other of the two copper export pumps (ATP7A or ATP7B) with no change in the HAH1 chaperone. We conclude that the acquisition of DDP resistance in ovarian carcinoma is accompanied by alterations in the cellular pharmacology of DDP that are paralleled by similar changes in the uptake and efflux of copper. These results are consistent with the concept that DDP enters and exits from the cell via transporters that normally mediate copper homeostasis.

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