2-Bromopalmitate sensitizes osteosarcoma cells to adriamycin-induced apoptosis via the modulation of CHOP
2-Bromopalmitate sensitizes osteosarcoma cells to adriamycin-induced apoptosis via the modulation of CHOP
复制标题
2-溴棕榈酸酯通过调节 CHOP 使骨肉瘤细胞对阿霉素诱导的细胞凋亡敏感
DOI：
10.1016/j.ejphar.2018.12.019
复制
发表时间：
2019-02-05
影响因子：
5
通讯作者：
Ying, Mei-dan
中科院分区：
文献类型：
--
作者：
Xu, Tong;Huang, Chao;Ying, Mei-dan
骨肉瘤是最常见的原发性恶性骨肿瘤，但自20世纪80年代中期以来，患者的生存率一直处于稳定状态。阿霉素是目前治疗骨肉瘤的一线化疗药物，但其剂量依赖性的严重副作用限制了其临床应用。在这里，我们提出了一个潜在的联合方案，其中阿霉素加2-溴棕榈酸酯，棕榈酰化抑制剂，表现出强大的治疗效果骨肉瘤。首先，2-溴棕榈酸酯强烈增加阿霉素在人骨肉瘤细胞系和原代骨肉瘤细胞中的增殖抑制。2-溴棕榈酸酯协同阿霉素诱导骨肉瘤细胞凋亡作用增强。我们的研究表明，活性氧清除剂NAG和GSH可以在很大程度上逆转阿霉素联合2-溴棕榈酸酯诱导的细胞凋亡，表明活性氧在这种联合治疗中起着重要作用。此外，联合组中CHOP显著升高，并且CHOP的沉默几乎完全阻断了2-溴棕榈酸酯和阿霉素联合诱导的凋亡。本研究为消除骨肉瘤提供了一种前瞻性的治疗策略，有利于临床联合治疗的发展。
Osteosarcoma is the most common primary malignant bone tumour, but the survival rate of patients has plateaued since the mid-1980s. Adriamycin is an integral component of the current first-line chemotherapies used for osteosarcoma, but dose-dependent severe side effects often limit its clinical application. Here, we propose a potential combination regimen in which adriamycin plus 2-bromopalmitate, a palmitoylation inhibitor, exhibited powerful therapeutic effects on osteosarcoma. First, 2-bromopalmitate strongly increased the proliferation inhibition of adriamycin in both human osteosarcoma cell lines and primary osteosarcoma cells. Adriamycin-induced apoptosis in osteosarcoma cells was enhanced when synergized with 2-bromopalmitate. Our study indicated that the reactive oxygen species scavenger NAG and GSH could largely reverse the apoptosis induced by adriamycin combined with 2-bromopalmitate, demonstrating that reactive oxygen species played an essential role in this combination therapy. Moreover, CHOP was remarkably elevated in the combination group, and silencing of CHOP almost completely blocked the apoptosis induced by the combination of 2-bromopalmitate and adriamycin. Taken together, our study provides a prospective therapeutic strategy to eliminate osteosarcoma, which is propitious to clinical combination therapy development.