骨肉瘤（OS）是一种原发性恶性骨肿瘤，具有转移频繁、病情进展快、死亡率高的特点。几十年来，OS 的治疗方案基本上没有变化，主要包括细胞毒性化疗和手术，因此迫切需要新的疗法。托酚酮是天然存在的七元非苯环芳香族化合物，对多种癌细胞类型具有抗增殖作用。 MO-OH-Nap 是一种 α-取代的托酚酮，具有铁螯合剂的活性。在这里，我们证明 MO-OH-Nap 激活未折叠蛋白反应 (UPR) 途径的所有三个臂，并诱导一组人类 OS 细胞系凋亡。与氯化铁或硫酸亚铁铵共孵育可完全防止 MO-OH-Nap 处理的 OS 细胞中诱导凋亡和 UPR 标记。 MO-OH-Nap 上调转铁蛋白受体 1 (TFR1) 蛋白水平，以及 TFR1、二价金属转运蛋白 1 (DMT1)、铁调节蛋白 (IRP1、IRP2)、铁转运蛋白 (FPN) 和锌转运蛋白 14 (ZIP14)转录水平，证明 MO-OH-Nap 对 OS 细胞中铁稳态途径的影响。此外，MO-OH-Nap 处理限制了 OS 细胞的体外迁移和侵袭。最后，MO-OH-Nap 处理的 OS 细胞的代谢组学分析揭示了嘌呤和嘧啶代谢的明显变化。总的来说，我们证明 MO-OH-Nap 在 OS 细胞中诱导的细胞毒性作用取决于托酚酮改变细胞铁可用性的能力，并且该药物利用了关键的代谢途径。这些研究支持进一步评估 MO-OH-Nap 作为 OS 的新型治疗方法。© 2023 作者。药物开发研究由 Wiley periodicals LLC 出版。

Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO-OH-Nap is an α-substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO-OH-Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co-incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO-OH-Nap-treated OS cells. MO-OH-Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron-regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO-OH-Nap on iron-homeostasis pathways in OS cells. Furthermore, MO-OH-Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO-OH-Nap-treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO-OH-Nap-induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO-OH-Nap as a novel treatment for OS.© 2023 The Authors. Drug Development Research published by Wiley Periodicals LLC.