Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou 310009, China.
Eur J Pharmacol. 2019 Feb 5;844:204-215. doi: 10.1016/j.ejphar.2018.12.019. Epub 2018 Dec 12.
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 NAC 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.
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，患者的生存率已趋于平稳。阿霉素是目前骨肉瘤一线化疗药物的重要组成部分，但剂量依赖性的严重副作用常常限制了其临床应用。在这里，我们提出了一种潜在的联合治疗方案，即阿霉素加 2-溴棕榈酸酯（一种棕榈酰化抑制剂），对骨肉瘤具有强大的治疗作用。首先，2-溴棕榈酸酯强烈增加了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作用。当与 2-溴棕榈酸酯协同作用时，阿霉素诱导的骨肉瘤细胞凋亡增强。我们的研究表明，活性氧清除剂 NAC 和 GSH 可以在很大程度上逆转阿霉素与 2-溴棕榈酸酯联合诱导的凋亡，表明活性氧在这种联合治疗中起着至关重要的作用。此外，CHOP 在联合组中明显升高，沉默 CHOP 几乎完全阻断了 2-溴棕榈酸酯和阿霉素联合诱导的凋亡。总之，我们的研究为消除骨肉瘤提供了一种有前景的治疗策略，有利于临床联合治疗的发展。
