A Photoactive Platinum(IV) Anticancer Complex Inhibits Thioredoxin-Thioredoxin Reductase System Activity by Induced Oxidization of the Protein

Inorg Chem. 2018 May 7;57(9):5575-5584. doi: 10.1021/acs.inorgchem.8b00529. Epub 2018 Apr 24.

Abstract

Thioredoxin (Trx) is an important enzyme in the redox signaling pathway and is usually overexpressed in tumor cells. We demonstrate herein that the photoactive platinum(IV) anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(Py)2] (1) can bind to His, Glu, and Gln residues of Trx upon the irradiation of blue light. More importantly, complex 1 can also induce the oxidation of Met, Trp, and the Cys catalytic sites to form disulfide bonds by generating reactive oxygen species (ROS) upon photoactivation. These eventually lead to inhibition of activity of Trx enzyme and the Trx system and further increase in the cellular ROS level. We speculate that the oxidative damage not only inhibits Trx activity but also greatly contributes to the anticancer action of complex 1.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Structure
  • Oxidation-Reduction / drug effects
  • Platinum Compounds / chemical synthesis
  • Platinum Compounds / chemistry
  • Platinum Compounds / pharmacology*
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
  • Thioredoxin-Disulfide Reductase / metabolism
  • Thioredoxins / antagonists & inhibitors*
  • Thioredoxins / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Platinum Compounds
  • TXN protein, human
  • Thioredoxins
  • Thioredoxin-Disulfide Reductase