Osteosarcoma (OSA) is the most common primary bone cancer in children, adolescents and dogs. Current combination surgical and chemotherapeutic treatments have increased survival. However, in recurrent or metastatic disease settings, the prognosis significantly decreases, representing an urgent need for better second‐line and novel chemotherapeutics. The current gold standard for combination chemotherapy in OSA often includes a platinum agent, for example, cisplatin or carboplatin. These platinum agents are shuttled within the cell via copper transporters. Recent interest in targeting copper transport has been directed towards antioxidant protein 1 (Atox1) and copper chaperone for superoxide dismutase 1 (CCS), with Atox1 demonstrating the ability to aggregate platinum agents, preventing them from forming DNA adducts. DC_AC50 is a small molecule inhibitor of both Atox1 and CCS. To assess the impact of targeting these pathways on chemotherapy response, two human and two canine OSA cell lines were utilized. After treatment with single agent or combination drugs, cell viability was evaluated and pharmacological synergism calculated using the combination index method. Apoptosis, cell cycle distribution, clonogenic survival and migration were also evaluated. DC_AC50 synergised with carboplatin in combination treatment of human and canine OSA cells to reduce cancer cell viability. DC_AC50‐treated cells were significantly less mitotically active, as demonstrated by decreased expression of phospho‐histone H3 and cell cycle analysis. DC_AC50 also potentiated carboplatin‐induced apoptosis in OSA cells and decreased clonogenic survival. Finally, DC_AC50 reduced the migratory ability of OSA cells. These results justify further investigation into inhibiting intracellular copper chaperones as a means of reducing/preventing acquired chemotherapy resistance.

中文翻译：

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铜伴侣蛋白的抑制使人和犬骨肉瘤细胞对卡铂化疗敏感。

骨肉瘤 (OSA) 是儿童、青少年和狗中最常见的原发性骨癌。目前的手术和化疗联合治疗提高了生存率。然而，在复发或转移性疾病的情况下，预后显着下降，这表明迫切需要更好的二线和新型化疗药物。目前 OSA 联合化疗的金标准通常包括铂类药物，例如顺铂或卡铂。这些铂剂通过铜转运蛋白在细胞内穿梭。最近对靶向铜转运的兴趣指向抗氧化蛋白 1 (Atox1) 和超氧化物歧化酶 1 (CCS) 的铜伴侣蛋白，Atox1 展示了聚集铂剂的能力，防止它们形成 DNA 加合物。DC_AC50 是 Atox1 和 CCS 的小分子抑制剂。为了评估靶向这些途径对化疗反应的影响，使用了两种人和两种犬 OSA 细胞系。用单一药剂或组合药物治疗后，评估细胞活力并使用组合指数法计算药理学协同作用。还评估了细胞凋亡、细胞周期分布、克隆存活和迁移。DC_AC50 与卡铂协同治疗人和犬 OSA 细胞以降低癌细胞活力。DC_AC50 处理的细胞的有丝分裂活性显着降低，磷酸组蛋白 H3 的表达降低和细胞周期分析证明了这一点。DC_AC50 还增强了卡铂诱导的 OSA 细胞凋亡并降低了克隆存活率。最后，DC_AC50 降低了 OSA 细胞的迁移能力。这些结果证明了进一步研究抑制细胞内铜伴侣蛋白作为减少/预防获得性化疗耐药性的一种手段是合理的。