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.

中文翻译：

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铜结合小分子诱导胶质母细胞瘤患者源性细胞中的氧化应激和细胞周期逮捕。

过渡金属是必不可少的，但其新陈代谢失调会导致毒性。在这里，我们报道化合物NSC319726与铜结合以诱导氧化应激并以皮摩尔浓度阻止胶质母细胞瘤患者来源的细胞。药物基因组学分析表明，NSC319726和65个其他结构类似物通过金属结合表现出致死性。尽管据报道NSC319726可以起锌离子载体的作用，但我们在此报道该化合物与铜结合以阻止细胞生长。我们产生并验证了药物基因组学预测：通过低氧诱导因子1α依赖性途径，低氧基本上抑制了铜的毒性。铜结合的NSC319726诱导了活性氧的产生和脱氧核糖基嘌呤的消耗，从而导致细胞周期停滞。