Regulation of the Cellular Pharmacology and Cytotoxicity of Cisplatin by Copper Transporters

Abstract

There is now a large body of evidence to indicate that the copper (Cu) transporters copper transporter receptor (CTR) 1, ATP7 A, and ATP7B regulate the cellular pharmacology and cytotoxicity of cisplatin (DDP), and that these proteins can mediate acquired DDP resistance. Cells that have acquired resistance to cisplatin demonstrate crossresistance to Cu and vice versa. The crossresistance between DDP and Cu is characterized by parallel changes in Cu and DDP accumulation and altered expression of the Cu efflux transporters ATP7A and ATP7B. Yeast, mouse, and human cells engineered to alter the expression of CTR1, ATP7A or ATP7B exhibit altered sensitivity to both Cu and DDP. Detailed studies of uptake and efflux indicate that each protein can alter the cellular pharmacology of DDP and in some cases, DDP analogs. Immunohistochemical studies of human tumors have identified associations between increased expression of either ATP7A or ATP7B and poor response to treatment with one or another of the platinum drugs. Whereas other transporters may also participate in the influx and efflux of the platinum drugs, available evidence supports the concept that DDP enters the cell, is distributed within the cell, and is exported by mechanisms that have evolved to manage Cu homeostasis.