a Department of Radiation Oncology , Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , China.
b Department of Orthopedic Oncology , Changzheng Hospital, Second Military Medical University , Shanghai , China.
Cell Cycle. 2018;17(8):997-1006. doi: 10.1080/15384101.2018.1467677. Epub 2018 Jun 25.
Osteosarcoma (OS) is the most prevalent bone malignancy in childhood and adolescence, with highly aggressive and early systemic metastases. Here, we reported that celecoxib, a selective COX-2 inhibitor in the NSAID class, exhibits strong antitumor activity in dose dependent manner in two OS cell lines-143B and U2OS. We showed that celecoxib inhibits OS cell growth, causes G0/G1-phase arrest, modulates apoptosis and autophagy and reduces migration in OS cells. In addition, the results of fluorescent mitochondrial probe JC-1 test indicated that the mitochondrial pathway mediates celecoxib-induced apoptosis. Significantly, the autophagy inhibitor CQ combined with celecoxib causes greater cell proliferation inhibition and apoptosis. Pharmacologic inhibition of autophagy with another potent autophagy inhibitor SAR405 also enhances celecoxib-mediated suppression of cell viability. These results were confirmed with shRNAs targeting the autophagy-related gene Atg5. In OS tumor xenografts in vivo, celecoxib also presents antitumor activity. Taken together, our results shed light on the function and mechanism of antitumor action of celecoxib for treatment of OS patients.
骨肉瘤（OS）是儿童和青少年中最常见的骨恶性肿瘤，具有高度侵袭性和早期全身转移的特点。在这里，我们报道了塞来昔布，一种 NSAID 类的选择性 COX-2 抑制剂，在两种骨肉瘤细胞系-143B 和 U2OS 中表现出剂量依赖性的强大抗肿瘤活性。我们表明塞来昔布抑制骨肉瘤细胞生长，导致 G0/G1 期阻滞，调节细胞凋亡和自噬，并减少骨肉瘤细胞的迁移。此外，荧光线粒体探针 JC-1 试验的结果表明线粒体途径介导塞来昔布诱导的细胞凋亡。值得注意的是，自噬抑制剂 CQ 与塞来昔布联合使用会导致更大的细胞增殖抑制和细胞凋亡。另一种有效的自噬抑制剂 SAR405 对自噬的药理抑制也增强了塞来昔布对细胞活力的抑制作用。这些结果通过靶向自噬相关基因 Atg5 的 shRNAs 得到了证实。在骨肉瘤肿瘤异种移植的体内实验中，塞来昔布也表现出抗肿瘤活性。总之，我们的研究结果揭示了塞来昔布治疗骨肉瘤患者的抗肿瘤作用的功能和机制。
