TY - JOUR T1 - The Copper Export Pump ATP7B Modulates the Cellular Pharmacology of Carboplatin in Ovarian Carcinoma Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 466 LP - 473 DO - 10.1124/mol.64.2.466 VL - 64 IS - 2 AU - Kuniyuki Katano AU - Roohangiz Safaei AU - Goli Samimi AU - Alison Holzer AU - Myriam Rochdi AU - Stephen B. Howell Y1 - 2003/08/01 UR - http://molpharm.aspetjournals.org/content/64/2/466.abstract N2 - 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 μM [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. ER -