Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells

Cell Chem Biol. 2018 May 17;25(5):585-594.e7. doi: 10.1016/j.chembiol.2018.02.010. Epub 2018 Mar 22.

Abstract

Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.

Keywords: copper; cytostasis; glioblastoma; mechanism of action; metal toxicity; oxidative stress; pharmacogenomics; purine deoxyribonucleosides; reactive oxygen species; systems biology.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Copper / metabolism*
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Male
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Thiosemicarbazones / chemistry*
  • Thiosemicarbazones / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Thiosemicarbazones
  • Copper