Transport of Cisplatin by the Copper Efflux Transporter ATP7B

  title={Transport of Cisplatin by the Copper Efflux Transporter ATP7B},
  author={Roohangiz Safaei and Shinji Otani and Barrett J. Larson and Michael L Rasmussen and Stephen B. Howell},
  journal={Molecular Pharmacology},
  pages={461 - 468}
ATP7B is a P-type ATPase that mediates the efflux of copper. Recent studies have demonstrated that ATP7B regulates the cellular efflux of cisplatin (DDP) and controls sensitivity to the cytotoxic effects of this drug. To determine whether DDP is a substrate for ATP7B, DDP transport was assayed in vesicles isolated from Sf9 cells infected with a baculovirus that expressed either the wild-type ATP7B or a mutant ATP7B that was unable to transport copper as a result of conversion of the… 

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Regulation of the Export of Platinum-Containing Drugs by the Copper Efflux Transporters ATP7A and ATP7B

It is demonstrated that, although less effective than Cu, DDP serves as a substrate of ATP7B, and plays a direct role in the transport of DDP.

Role of copper transporters in resistance to platinating agents

Evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin and examined whether O6-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of Cells with or without the transporter, finding no change in total cytoplasmic platinum levels following treatment with BG plus cisplasin.

The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin.

It is demonstrated that ATP7B can confer resistance to cisplatin by sequestering the drug in its N-terminal metal-binding domain without active drug extrusion from the cell.

Functional Interactions of Cu-ATPase ATP7B with Cisplatin and the Role of ATP7B in the Resistance of Cells to the Drug*

The results support functional interactions between cisplatin and ATP7B but argue against the active transport through the copper translocation pathway as a mechanism of drug resistance.

Sec61β Controls Sensitivity to Platinum-Containing Chemotherapeutic Agents through Modulation of the Copper-Transporting ATPase ATP7A

It is concluded that Sec61β modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs.

The role of metal binding and phosphorylation domains in the regulation of cisplatin-induced trafficking of ATP7B.

Results demonstrate that the CXXC motif in the sixth MBD and the catalytic activity of ATP7B are required for cDDP-induced trafficking as they are for Cu-induced redistribution of ATP 7B; this provides further evidence that cD DP mimics Cu with respect to the molecular mechanisms by they control the subcellular distribution of ATP6B.

ATP7B expression confers multidrug resistance through drug sequestration

It is demonstrated that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration of doxorubicin, thereby attenuating drug resistance and suggesting that the sequestration depends on the acids of the vesicles partly.

Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B

SSM measurements demonstrated that electrogenic copper displacement occurs within ATP7A/B following addition of ATP and formation of the phosphorylated intermediate, suggesting that net proton counter‐transport may not occur in copper ATPases.

Translocation of platinum anticancer drugs by human copper ATPases ATP7A and ATP7B.

Experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar to that of Cu.

Mechanism of tumor resistance to cisplatin mediated by the copper transporter ATP7B.

  • O. Dmitriev
  • Chemistry, Biology
    Biochemistry and cell biology = Biochimie et biologie cellulaire
  • 2011
Transient platinum sequestration in the metal-binding domain followed by transfer to an acceptor protein or a low molecular weight compound is proposed as an alternative mechanism of cisplatin detoxification in the cell.



Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance.

Transfected the copper-transporting P-type ATPase cDNA into human epidermoid carcinoma KB-3-1 cells and found that KB/WD cells were sensitive to other heavy metals, such as antimony, arsenate, arsenite, cadmium, and cobalt, and ATP7B may be involved in cisplatin resistance in some tumors.

Confocal Microscopic Analysis of the Interaction between Cisplatin and the Copper Transporter ATP7B in Human Ovarian Carcinoma Cells

Evidence is provided that DDP directly interacts with ATP7B to trigger its relocalization and that ATP7b mediates resistance to DDP by sequestering it into vesicles of the secretory pathway for export from the cell.

Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B.

Both ATP7A and ATP7B modulate the pharmacodynamics of all three clinically used platinum drugs, demonstrating that these copper exporters sequester the platinum drugs into subcellular compartments, limiting their cytotoxicity, similar to their effect on copper.

The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells.

It is concluded 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.

Role of copper transporters in the uptake and efflux of platinum containing drugs.

Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.

Role of Na+, K+-ATPase α1 subunit in the intracellular accumulation of cisplatin

The results suggest that Na+, K+-ATPase-dependent active transport of CDDP does not occur in resistant cells, and the findings provide the first evidence that the Na+,K+- ATPase α1 subunit plays an important role in the transport ofCDDP.

Functional Properties of the Copper-transporting ATPase ATP7B (The Wilson's Disease Protein) Expressed in Insect Cells*

A baculovirus-mediated expression system for WNDP is developed, which permits direct and quantitative analysis of catalytic properties of this protein and provides experimental evidence that it has functional properties characteristic of a P-type ATPase.

Characterization of Mg2+-ATPase activity in isolated B16 murine melanoma melanosomes

B16 murine melanoma melanosomes were purified using sucrose density gradient centrifugation. ATPase activity was evaluated in presence of specific ATPase inhibitors, and compared with melanosome

Characterization of a P-type Copper-Stimulated ATPase from Mouse Liver

Mouse liver microsomes treated with octylthioglucoside (OTG-microsomes) were examined for copper-stimulated ATPase activity and it is suggested that microsome from mouse liver contain copper/iron- Stimulated P-type ATPase.