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 ϩ/ϩ ) and a subline in which both alleles of CTR1 were deleted (CTR1

Combined modalities of resistance in an oxaliplatin-resistant human gastric cancer cell line with enhanced sensitivity to 5-fluorouracil

“…Song et al (2004) recently showed that transfection of CTR1 into a CDDP-resistant, CTR1-deficient subline of a small-cell lung cancer cell line enhanced cellular uptake of all platinum compounds and increased sensitivity to CDDP and carboplatin, but not to oxaliplatin. Holzer et al (2006) demonstrated that CTR1 controls the cellular accumulation of CDDP, carboplatin, and oxaliplatin at low concentrations. However, accumulation of oxaliplatin is not dependent on CTR1 at higher concentrations.…”

Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin

“…Acquired resistance to platinum compounds has been recently related to restoration of BRCA1/2 expression and homologous recombination function in tumors with frame-shift mutations of such genes [14]. Cells that have acquired resistance to cisplatin often have impaired drug uptake [15] and this has been linked to altered expression of genes involving copper metabolism [16][17][18][19][20][21]. Additional studies have implicated members of the ATP binding cassette (ABC) family of transporters such as Multidrug resistance associated protein (MRP) 2 and MRP1 in the accumulation defects found in cisplatin-resistant cells [22,23].…”

Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein1

“…Subsequently, Howell et al observed that oxaliplatin at higher concentrations may use a different cellular entry mechanism. 15 In addition to these conventional mononuclear Pt drugs, an experimental polynuclear Pt compound BBR3464 has also been demonstrated to utilize hCtr1 to gain cellular access. 16 Studies of a variety of human cell lines in which hCtr1 is over-expressed reveal that simply increasing the level of hCtr1 does not always correlate with an increase in cell death by Pt drugs.…”

“…18 However, because it is not clear that over-expressed Ctr1 functions normally in human cells, it is not at all obvious that its forced over-expression should be expected to lead to an increase in Pt accumulation. 15 More conflicting results describe the trafficking of Ctr1 in the presence of Pt drugs. In human ovarian carcinoma cells that endogenously or exogenously express hCtr1, cisplatin causes rapid disappearance of the transporter from the plasma membrane, suggesting that cisplatin down-regulates its own transporter in these cells.…”