title: The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells.
abstract: Human tumor cells lines with acquired resistance to cisplatin (DDP) and carboplatin (CBDCA) are often cross-resistant to copper and vice versa, and some DDP-resistant cells overexpress the copper export pump ATP7B. We sought to demonstrate that ATP7B directly mediates resistance to DDP and CBDCA by stably transfecting human carcinoma cells with a vector designed to express ATP7B. Increased expression of ATP7B rendered all three cell lines tested more resistant to a 1-h exposure to DDP (1.6-2.6-fold), CBDCA (1.5-1.6-fold), and copper (1.2-1.4-fold). The effect of ATP7B on the cellular pharmacology of 64Cu and [14C]CBDCA was investigated in more detail using one cell pair (2008 cells transfected with an empty vector or an ATP7B-expressing vector). In the 2008/ATP7B subline, steady-state copper levels were decreased under both basal and copper-supplemented conditions, as was steady-state CBDCA content upon exposure to 50 microM [14C]CBDCA. Over the first 5 min, the average rate of accumulation of copper and CBCDA in the 2008/ATP7B cells was reduced by 37 and 61%, respectively. Efflux was more rapid from 2008/ATP7B cells for both copper and CBDCA. Two-compartment modeling indicated that the second phase of efflux was increased by a factor of 3.9-fold for CBCDA and to an even greater extent for copper. We conclude that expression of ATP7B regulates sensitivity to CBDCA as well as to DDP and copper and that a transporter that normally mediates copper homeostasis modulates the cellular pharmacology of CBDCA.
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0058, USA.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Katano
authors.forename: Roohangiz
authors.initials: R
authors.lastname: Safaei
authors.forename: Goli
authors.initials: G
authors.lastname: Samimi
authors.forename: Alison
authors.initials: A
authors.lastname: Holzer
authors.forename: Myriam
authors.initials: M
authors.lastname: Rochdi
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000502:physiology*; D003300:Copper; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D003300:Copper; D016190:Carboplatin; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases