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

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.

• Authors: Kenichi Shimada, Eduard Reznik, Michael E Stokes, Lakshmi Krishnamoorthy, Pieter H Bos, Yuyu Song, Christine E Quartararo, Nen C Pagano, Darren R Carpizo, Ana C deCarvalho, Donald C Lo, Brent R Stockwell
• Journal: Cell chemical biology (Cell Chem Biol) Vol. 25 Issue 5 Pg. 585-594.e7 (05 17 2018) ISSN: 2451-9448 [Electronic] United States
• PMID: 29576531 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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