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.

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters

“…From the anticancer therapy point of view, the complex formation of TSC with copper(II) is intriguing, as cancers cells rely upon higher intracellular levels of copper relative to healthy cells, to promote angiogenesis, tumour growth and metastasis [ 80 , 81 , 82 ]. The cytotoxic effect of the most potent TSCs, for example, Dp44mT [ 40 , 83 ] and NSC-319726 [ 84 ] in cancer cells is potentiated by chelation to copper(II). Analogous behaviour was also reported for proline and morpholine substituted TSCs hybrids [ 21 , 24 ].…”

Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53

“…One clearly must be alert to off-target toxicity caused by ZMC-mediated ROS, although these effects are not always undesirable. The aforementioned ZMC1-copper study found that ZMC1 arrested patient-derived glioblastoma cells at picomolar concentrations, due to ROS-induced depletion of deoxyribosyl purines [56].…”

“…ROS stimulates damage response pathways that post-translationally modify p53 to enhance its nuclear entry, recruitment of transcriptional machinery, and resistance to turnover [55]. Zinc ions exist only in a single oxidation state and cannot generate ROS, but it was shown that ZMC1 binds copper ions in the cell and creates ROS by as-yet uncharacterized reactions [56]. In agreement, cellular ROS scavengers such as N-acetyl cysteine do not affect ZMC1's power to refold mutant p53, but inhibit the ability of the newly-reconformed protein to carry out its transcriptional program [23].…”

Clinical and Research Applications of a Brain Tumor Tissue Bank in the Age of Precision Medicine

“…The models presented remarkable heterogeneity and conservation of the original somatic genomic alterations including extrachromosomal oncogene amplification [40]. The HBTB CSC and PDX models are used in basic research and preclinical studies focused on precision medicine in internal and collaborative projects involving academic, nonprofit and pharmaceutical industry studies [41–43].…”