Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
Vet Comp Oncol. 2020 Dec;18(4):559-569. doi: 10.1111/vco.12579. Epub 2020 Mar 20.
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.
骨肉瘤（OSA）是儿童、青少年和犬类中最常见的原发性骨癌。目前的联合手术和化疗治疗已经提高了生存率。然而，在复发性或转移性疾病环境中，预后显著下降，这代表着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。这些铂类药物通过铜转运体在细胞内穿梭。最近，人们对靶向铜转运的兴趣集中在抗氧化蛋白 1（Atox1）和超氧化物歧化酶 1 的铜伴侣（CCS）上，Atox1 具有聚集铂类药物的能力，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，使用了两种人源和两种犬源 OSA 细胞系。在用单药或联合药物处理后，通过组合指数法评估细胞活力和计算药理协同作用。还评估了细胞凋亡、细胞周期分布、集落形成存活和迁移。DC_AC50 与卡铂联合治疗人源和犬源 OSA 细胞，协同降低癌细胞活力。与对照组相比，DC_AC50 处理的细胞有丝分裂活性显著降低，表现为磷酸化组蛋白 H3 的表达减少和细胞周期分析。DC_AC50 还增强了 OSA 细胞中卡铂诱导的细胞凋亡，并降低了集落形成存活。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作为减少/预防获得性化疗耐药的方法是合理的。
