title: Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin.
abstract: The goal of this study was to determine the ability of the major copper influx transporter CTR1 to mediate the cellular accumulation of cisplatin (DDP), carboplatin (CBDCA), and oxaliplatin (L-OHP). Wild-type murine embryonic fibroblasts (CTR1+/+) and a subline in which both alleles of CTR1 were deleted (CTR1-/-) were tested for their ability to accumulate platinum when exposed to increasing concentrations of DDP, CBDCA, or L-OHP for 1 h. They were also tested for their sensitivity to the growth-inhibitory effect of each drug. Platinum content was measured by ion-coupled plasmon mass spectroscopy. The experimental model was validated by measuring copper accumulation and cytotoxicity. CTR1-/- cells accumulated only 5.7% as much copper as CTR1+/+ cells during a 1-h exposure to 2 microM copper. When exposed to DDP, CBDCA, or L-OHP at 2 microM, accumulation in the CTR1-/- cells was only 35 to 36% of that in the CTR1+/+ cells. When tested at a 5-fold higher concentration, this deficit remained for DDP and CBDCA, but accumulation of L-OHP was no longer CTR1-dependent. There was an association between the effect of loss of CTR1 function on uptake of the platinum drugs and their cytotoxicity. The CTR1-/- cells were 3.2-fold resistant to DDP, 2.0-fold resistant to CBDCA, but only 1.7-fold resistant to L-OHP. Thus, whereas CTR1 controls the cellular accumulation of all three drugs at low concentrations, accumulation of L-OHP is not dependent on CTR1 at higher concentrations. We conclude that L-OHP is a substrate for some other cellular entry mechanism, a feature consistent with its different clinical spectrum of activity.
authors.affiliation: Department of Medicine and the Rebecca and John Moores UCSD Cancer Center, 3855 Health Sciences Drive, Room 3344, La Jolla, CA 92093-0819, USA.
authors.forename: Alison K
authors.initials: AK
authors.lastname: Holzer
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Manorek
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016190:Carboplatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D003300:Copper / Q000493:pharmacokinetics; D000079923:Copper Transporter 1; D051379:Mice; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077150:Oxaliplatin; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D009944:Organoplatinum Compounds; C490079:SLC31A1 protein, human; D000077150:Oxaliplatin; D003300:Copper; D016190:Carboplatin; D002945:Cisplatin