2,5-Dimethyl-celecoxib (DMC) is a close structural analog of the selective COX-2 inhibitor celecoxib that lacks COX-2-inhibitory function. Thus, DMC is a promising drug for anti-tumor. In this study, we evaluated the efficacy and the molecular basis of DMC in the treatment of human glioblastoma multiforme (GBM). DMC inhibited the growth and proliferation of GBM cell lines (LN229, A172, U251, and U87MG) in a dose-dependent manner (P < 0.001). In GBM cells treated with DMC, detection by flow cytometry showed cell cycle arrest, and proteins involved in cell cycle such as P21 were increased. Compared with control group, Annexin-V/PI-staining in DMC-treatment group was increased, indicating that DMC could induce apoptosis in GBM cells. Also, associated proteins including cleaved caspase 3 and cleaved PARP-1 were increased. It was further explored whether DMC blocked cell cycle and induced apoptosis in GBM cells through CIP2A/PP2A/AKT signaling pathway. After treatment of DMC, the phosphorylation of Akt was reduced while the total Akt level was not affected. DMC suppressed the expression of CIP2A in a time-dependent manner, while the CIP2A overexpression group reversed cell cycle and apoptotic protein expression led by DMC. Finally, in a xenograft model in nude mice using LN229 cells, DMC suppressed tumor growth. These findings proved that DMC could block cell cycle and induce apoptosis in GBM cells by suppressing CIP2A/PP2A/Akt signaling axis, which indicated that DMC could be an effective option for GBM treatment.

2,5-二甲基-塞来昔布 (DMC) 是选择性 COX-2 抑制剂塞来昔布的紧密结构类似物，缺乏 COX-2 抑制功能。因此，DMC是一种很有前景的抗肿瘤药物。在这项研究中，我们评估了 DMC 在治疗人多形性胶质母细胞瘤 (GBM) 中的疗效和分子基础。DMC 以剂量依赖性方式抑制 GBM 细胞系（LN229、A172、U251 和 U87MG）的生长和增殖（P < 0.001)。在用 DMC 处理的 GBM 细胞中，流式细胞术检测显示细胞周期停滞，参与细胞周期的蛋白质如 P21 增加。与对照组相比，DMC处理组Annexin-V/PI染色增加，说明DMC可诱导GBM细胞凋亡。此外，包括裂解的 caspase 3 和裂解的 PARP-1 在内的相关蛋白增加。进一步探讨DMC是否通过CIP2A/PP2A/AKT信号通路阻断细胞周期并诱导GBM细胞凋亡。DMC处理后，Akt的磷酸化降低，而总Akt水平不受影响。DMC 以时间依赖性方式抑制 CIP2A 的表达，而 CIP2A 过表达组逆转了由 DMC 领导的细胞周期和凋亡蛋白表达。最后，在使用 LN229 细胞的裸鼠异种移植模型中，DMC 抑制了肿瘤生长。这些发现证明DMC可以通过抑制CIP2A/PP2A/Akt信号轴来阻断细胞周期并诱导GBM细胞凋亡，表明DMC可能是治疗GBM的有效选择。