Translocation of Platinum Anticancer Drugs by Human Copper ATPases ATP7A and ATP7B

Abstract

Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance, a phenomenon not entirely understood, with contribution of drug detoxification, defective accumulation, and efflux from the cell. Down-regulation of CTR1, responsible for Cu uptake by the cell, and up-regulation of the Cu-ATPases, ATP7A and ATP7B, which accept Cu from the cytosolic chaperone Atox1 and transfer the metal ion into the secretory pathway where it is incorporated into cuproenzymes, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, adsorbed on a solid supported membrane (SSM). The experimental results demonstrate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation with a mechanism identical to that of Cu. We then used NMR spectroscopy and ESI-MS to determine the binding mode of these drugs to the first N-terminal metal binding domain of ATP7A (Mnk1).

Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin

“…Therefore, if a reduction in drug accumulation in the cytoplasm does contribute to resistance development, this is much more likely to come about via an increase in the rate of efflux of the drug out of the cell. Evidence supporting such a mechanism has recently been presented by Tadini-Buoninsegni et al, 35 who…”

Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs

“…The formation of adducts with "naked" Pt was already observed in the case of direct reaction between cisplatin and apoMets7 or apoMnk1 [32,46]. In contrast, in the case of oxaliplatin, that contains the more stable chelating cyclohexane-1R,2R-diamine (dach) ligand, the "Pt(dach)" moiety was maintained intact after interaction with the model proteins [47].…”

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

“…Thus, both ATP7A and ATP7B play important roles in regulating cellular Cu homeostasis by eliminating excess Cu. The N-terminal CXXC motifs are also involved in Pt binding in cDDP treatments [43, 44]. However, whether the platination involves Atox1-bound cDDP is not clear.…”