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

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 a HIF-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of purine deoxyribonucleosides, 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 new potent mechanism for targeting glioblastomas.