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

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

Author information

1
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
2
Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, CA 94720, USA.
3
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
4
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
5
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, USA.
6
Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
7
Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.

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

PMID:
29576531
PMCID:
PMC5959763
DOI:
10.1016/j.chembiol.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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