Cross-resistance to cisplatin in cells with acquired resistance to copper.
OBJECTIVE
Cells selected for resistance to cisplatin (DDP) demonstrate cross-resistance to copper (Cu) suggesting one or more common mechanisms of cellular defense. We sought to determine whether cells selected for resistance to Cu are cross-resistant to DDP.


METHODS
Parental HuH7 human hepatoma cells and the CuR27 Cu-resistant subline were compared for sensitivity to Cu and DDP by clonogenic assay, and with respect to drug uptake and efflux by measuring cellular Cu and Pt content.


RESULTS
CuR27 cells were found to be 1.8-fold resistant to Cu and 8.6-fold cross-resistant to DDP. Changes in the cellular pharmacokinetics of Cu in the CuR27 cells were paralleled by changes in the kinetics of DDP. The accumulations of Cu and DDP measured at 1 min were, respectively, 36% and 26% of those in the parental HuH7 cells. The initial rate of efflux from the CuR27 cells was 6.2-fold faster for Cu and 2.5-fold faster for DDP than from the HuH7 cells. Cu reduced the accumulation of DDP in the HuH7 cells in a concentration-dependent manner and vice versa. DDP also reduced the efflux of Cu. Western blot analysis demonstrated that expression of the Cu exporter ATP7B was increased 3.9-fold in the CuR27 cells.


CONCLUSIONS
In this model system, cross-resistance between Cu and DDP was bidirectional and accompanied by parallel changes in the cellular pharmacokinetics of both compounds. The results are consistent with the idea that transporters and chaperones that normally mediate Cu homeostasis also directly or indirectly modulate the accumulation of DDP.
Safaei
Roohangiz
R
Department of Medicine 0058, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0058, USA.
Katano
Kuniyuki
K
Samimi
Goli
G
Naerdemann
Wiltrud
W
Stevenson
Jennifer L
JL
Rochdi
Myriam
M
Howell
Stephen B
SB
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D000073840:Copper-Transporting ATPases; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D002945:Cisplatin