title: Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper.
abstract: Impaired uptake of cisplatin (DDP) consistently accompanies the acquisition of resistance to the platinum drugs. The pathways by which DDP enters or 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.
authors.affiliation: Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California 92093-0058, USA.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Katano
authors.forename: Akira
authors.initials: A
authors.lastname: Kondo
authors.forename: Roohangiz
authors.initials: R
authors.lastname: Safaei
authors.forename: Alison
authors.initials: A
authors.lastname: Holzer
authors.forename: Goli
authors.initials: G
authors.lastname: Samimi
authors.forename: Misako
authors.initials: M
authors.lastname: Mishima
authors.forename: Yien-Ming
authors.initials: YM
authors.lastname: Kuo
authors.forename: Myriam
authors.initials: M
authors.lastname: Rochdi
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D003300:Copper / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D019327:Copper Sulfate / Q000493:pharmacokinetics / Q000494:pharmacology; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D056511:Metallochaperones; D018832:Molecular Chaperones; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
chemical_list: C474500:ATOX1 protein, human; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D000079923:Copper Transporter 1; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; C490079:SLC31A1 protein, human; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D019327:Copper Sulfate; D002945:Cisplatin