Reaction of platinum anticancer drugs and drug derivatives with a copper transporting protein, Atox1

Biochem Pharmacol. 2012 Apr 1;83(7):874-81. doi: 10.1016/j.bcp.2012.01.018. Epub 2012 Jan 21.


Platinum (Pt) containing anticancer drugs have been used in cancer treatment for several decades as they trigger cell death upon DNA binding. Pt-containing anticancer drugs and drug derivates with a variety of ligands around the Pt center (with Cisplatin being most well known) exist today in clinics and in clinical trials. However, a major drawback with these drugs is limited efficacy due to side reactions resulting in cell resistance. The cellular copper (Cu) transport pathway is proposed to be responsible for part of these side reactions through interactions with the Pt-containing drugs and possibly cellular export of Pt. The cytoplasmic Cu chaperone, Atox1, was recently found to bind Cisplatin in vitro and, when over-expressed in Escherichia coli, in vivo. Here we investigate how the chemical properties of six Pt-substances differentially affect binding, unfolding, and aggregation of Atox1 in vitro using near- and far-UV circular dichroism (CD) spectroscopy and SDS-PAGE. The results show that both ligand type and orientation dictate the interactions with Atox1. Only substances with two good leaving groups in cis-configuration result in near-UV CD changes that report on Cu-Pt interactions. The different substances promote Atox1 unfolding in a pattern that can be explained by ligand chemistry and geometry. Our work emphasize that ligands around the Pt-center have decisive roles in tuning protein interactions (prior to DNA binding) and therefore they also dictate the level of drug side effects and cellular resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / chemistry
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cation Transport Proteins / chemistry*
  • Cation Transport Proteins / metabolism*
  • Circular Dichroism
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Ligands
  • Metallochaperones
  • Models, Molecular
  • Molecular Chaperones / chemistry*
  • Molecular Chaperones / metabolism*
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Platinum Compounds / chemistry
  • Platinum Compounds / pharmacology*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Unfolding


  • ATOX1 protein, human
  • Cation Transport Proteins
  • Ligands
  • Metallochaperones
  • Molecular Chaperones
  • Organoplatinum Compounds
  • Platinum Compounds