Background:Ewing sarcoma (ES) is an aggressive malignancy and there is an unmet need for more effective treatment options for patients. Histone deacetylases (HDACs) have been shown to be involved in ES tumorigenesis and HDAC inhibitors have been investigated in the context of ES. Our objective for this study was to investigate the efficacy and mechanism of action of HDAC inhibition in vitro and in vivo in ES models, alone and in combination with standard of care therapies.Methods/Results:HDAC inhibitors were tested for in vitro efficacy against ES cell lines and romidepsin was found to be most effective. The mechanistic changes induced by romidepsin were investigated by Western blotting and proteins involved in cell cycle progression and DNA damage repair were found to be repressed. In vitro we identified that romidepsin synergizes with doxorubicin and etoposide and that it increases the efficacy of the standard of care combinations VDC/IE. Further, the combination treatments lead to an increase in caspase 3/7 cleavage, a decrease in DNA damage repair proteins, and an accumulation of DNA damage. In vivo, the combination of romidepsin and ifosfamide/etoposide (IE) leads to a significant decrease in tumor volume compared to that of IE alone.Conclusions:Our data indicates that romidepsin improves efficacy of chemotherapeutic agents in vitro and leads to a decreased tumor volume in vivo, suggesting that the addition of romidepsin may improve upfront treatment in ES patients.
背景：尤文肉瘤是一种侵袭性恶性肿瘤，目前临床上对更有效治疗方案的需求尚未得到满足。研究表明组蛋白去乙酰化酶参与尤文肉瘤的肿瘤发生过程，且HDAC抑制剂已在尤文肉瘤治疗领域得到研究。本研究旨在探讨HDAC抑制剂在尤文肉瘤模型中（包括单药治疗及与标准治疗方案联合应用）的体外和体内疗效及其作用机制。 方法与结果：通过体外实验评估HDAC抑制剂对尤文肉瘤细胞系的疗效，发现罗米地辛作用最为显著。Western blotting检测显示罗米地辛可抑制细胞周期进程和DNA损伤修复相关蛋白的表达。体外实验证实罗米地辛与多柔比星及依托泊苷具有协同作用，并能增强标准联合方案VDC/IE的疗效。联合治疗可促进caspase 3/7的切割、降低DNA损伤修复蛋白水平并导致DNA损伤累积。在动物实验中，罗米地辛联合异环磷酰胺/依托泊苷方案较单用IE方案能显著降低肿瘤体积。 结论：研究数据表明罗米地辛在体外能增强化疗药物疗效，在体内可显著缩小肿瘤体积，提示在尤文肉瘤患者的初始治疗方案中加入罗米地辛可能提升治疗效果。
肿瘤(癌症)患者之家