Platinum drugs, copper transporters and copper chelators

Cisplatin has been used since the end of 1970s as chemotherapeutic agent for a variety of tumors; however, its efficacy is limited by severe side effects and the rapid onset of resistance mechanisms, which include reduced drug uptake and increased efflux and sequestration. A yeast genetic screen for cisplatin-resistant mutants identified the copper transporter CTR1 as a mediator of cisplatin uptake. However, cisplatin binding to methionine-rich motifs, located in the N-terminal extracellular region of the protein, is accompanied by fast displacement of ammine ligands that are considered essential for the anticancer activity. Cisplatin also binds to CxxC motifs of Cu export pumps, ATP7A and ATP7B, and undergoes ATP-dependent translocation. In the presence of both Cu and cisplatin, translocation is inhibited for both metallic species. Increased drug resistance is associated to down-regulation of CTR1 and up-regulation of Cu-ATPases and Cu-chaperone Atox1, which is crucial for Cu secretion. The ability of Cu-lowering agents, such as tetrathiomolybdate, to increase cisplatin uptake, down-regulate Cu-ATPases and inhibit platination of Cu-Atox1 may resensitize cisplatin-resistant cells and improve the treatment efficacy of platinum drugs.