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

Angew Chem Int Ed Engl. 2014 Jan 27;53(5):1297-301. doi: 10.1002/anie.201307718. Epub 2013 Dec 27.

Abstract

Cisplatin, carboplatin, and oxaliplatin are widely used anticancer drugs. Their efficacy is strongly reduced by development of cell resistance. Down-regulation of CTR1 and up-regulation of the Cu-ATPases, ATP7A and ATP7B, have been associated to augmented drug resistance. To gain information on translocation of Pt drugs by human Cu-ATPases, we performed electrical measurements on the COS-1 cell microsomal fraction, enriched with recombinant ATP7A, ATP7B, and selected mutants, and adsorbed on a solid supported membrane. The experimental results indicate that Pt drugs activate Cu-ATPases and undergo ATP-dependent translocation in a fashion similar 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).

Keywords: ATPases; NMR spectroscopy; charge measurements; copper; platinum drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Motifs
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / toxicity
  • COS Cells
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Chlorocebus aethiops
  • Cisplatin / chemistry*
  • Cisplatin / metabolism
  • Cisplatin / toxicity
  • Copper / chemistry
  • Copper / metabolism
  • Copper Transporter 1
  • Copper-Transporting ATPases
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Magnetic Resonance Spectroscopy
  • Microsomes / metabolism
  • Mutagenesis, Site-Directed
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / metabolism
  • Organoplatinum Compounds / toxicity
  • Oxaliplatin
  • Protein Binding
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Spectrometry, Mass, Electrospray Ionization
  • Up-Regulation / drug effects

Substances

  • Antineoplastic Agents
  • Cation Transport Proteins
  • Copper Transporter 1
  • Intracellular Signaling Peptides and Proteins
  • Organoplatinum Compounds
  • Recombinant Proteins
  • SLC31A1 protein, human
  • Oxaliplatin
  • Copper
  • Adenosine Triphosphate
  • MKNK1 protein, human
  • Protein Serine-Threonine Kinases
  • Adenosine Triphosphatases
  • ATP7A protein, human
  • ATP7B protein, human
  • Copper-Transporting ATPases
  • Cisplatin