Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin
Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin
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DOI：
10.1002/prp2.632
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发表时间：
2020-08-01
影响因子：
2.6
通讯作者：
Okada, Hitoshi
中科院分区：
文献类型：
--
作者：
Oka, Naohiro;Komuro, Akiyoshi;Okada, Hitoshi
骨肉瘤（OS）是最常见的恶性骨肿瘤，也是儿童和青少年癌症相关死亡的主要原因。当前 OS 的标准治疗是术前化疗、手术切除和辅助化疗的组合。顺铂作为OS治疗的标准化疗药物，但其会引起多种不良反应，限制了其临床应用。希望在不增加顺铂剂量的情况下提高治疗效果。在本研究中，我们使用培养的人类 OS 细胞评估了抗坏血酸对顺铂治疗的综合作用。与抗坏血酸共同治疗可诱导对 OS 细胞的更大抑制，但不会对非恶性细胞增殖产生抑制。抗坏血酸对顺铂治疗的化疗增敏作用与 ROS 的产生密切相关。由于 ROS 产生增加而改变了细胞氧化还原状态，从而改变了 OS 细胞中的糖酵解和线粒体功能。此外，OS细胞球形成显着减少，表明抗坏血酸提高了顺铂对癌细胞群中干细胞样细胞的治疗功效。我们还发现，增强的 MYC 信号传导、核糖体生物合成、糖酵解和线粒体呼吸是具有顺铂耐药性的 OS 细胞的关键特征。此外，抗坏血酸可逆转顺铂耐药性。总而言之，我们的研究结果为在 OS 治疗策略中联合使用顺铂和抗坏血酸提供了理论依据。
Osteosarcoma (OS) is the most common malignant bone tumor and a leading cause of cancer-related deaths in children and adolescents. Current standard treatments for OS are a combination of preoperative chemotherapy, surgical resection, and adjuvant chemotherapy. Cisplatin is used as the standard chemotherapeutic for OS treatment, but it induces various adverse effects, limiting its clinical application. Improving treatment efficacy without increasing the cisplatin dosage is desirable. In the present study, we assessed the combined effect of ascorbate on cisplatin treatment using cultured human OS cells. Co-treatment with ascorbate induced greater suppression of OS cell but not nonmalignant cell proliferation. The chemosensitizing effect of ascorbate on cisplatin treatment was tightly linked to ROS production. Altered cellular redox state due to increased ROS production modified glycolysis and mitochondrial function in OS cells. In addition, OS cell sphere formation was markedly decreased, suggesting that ascorbate increased the treatment efficacy of cisplatin against stem-like cells in the cancer cell population. We also found that enhanced MYC signaling, ribosomal biogenesis, glycolysis, and mitochondrial respiration are key signatures in OS cells with cisplatin resistance. Furthermore, cisplatin resistance was reversed by ascorbate. Taken together, our findings provide a rationale for combining cisplatin with ascorbate in therapeutic strategies against OS.