少突胶质细胞前体细胞（OPC）的异常生长显着促进胶质母细胞瘤的进展。因此，阻断 OPC 生长的分子可能对治疗神经胶质瘤具有重要的治疗意义。 2-甲氧基雌二醇 (2ME) 是雌二醇的一种内源性微管蛋白相互作用代谢物，可有效对抗多种增殖性疾病。基于其抗癌和抗血管生成作用，目前正在进行II期临床试验。我们假设 2ME 可能通过靶向 OPC 生长来预防神经胶质瘤生长。在这里，我们通过评估 2ME 对 OPC 系“Oli-neu”生长的影响来检验这一假设，并剖析了潜在的机制。 2ME 处理以浓度依赖性方式抑制 OPC 生长，同时显着上调细胞周期负调节因子 p21 和 p27 的表达。此外，2ME 处理改变了 OPC 形态，从多臂突起变为圆形细胞。在 1uM 或更高的浓度下，2ME 诱导细胞凋亡，同时 caspase 3、PARP 和 caspase-7 片段的表达增加、外化磷脂酰丝氨酸染色/APOPercentage 以及线粒体活性增加。流式细胞术和显微镜分析表明，2ME 以浓度依赖性方式触发核内复制。重要的是，2ME 诱导细胞周期蛋白 E、JNK1/2 和 p53 表达以及 OPC 融合，这是驱动核内复制和全基因组复制的关键机制。重要的是，用pifithrin-α抑制p53可以挽救2ME诱导的核内复制。 2ME 的促凋亡和内复制作用伴随着生存素、细胞周期蛋白 A、细胞周期蛋白 B、细胞周期蛋白 D2 和 ppRB 的上调。在 CG4 细胞中观察到 2ME 具有类似的生长抑制、细胞凋亡和核内复制作用。总而言之，我们的研究结果提供了证据，表明 2ME 不仅抑制 OPC 生长并引发细胞凋亡，而且还激活 OPC 进入生存（战斗或逃跑）模式，从而导致核内复制。正如许多微管蛋白相互作用药物所观察到的那样，OPC 的这种固有的生存特征可能在一定程度上导致了神经胶质瘤的耐药性。重要的是，2ME 处理后 OPC 的命运可能取决于单个细胞的细胞周期状态。将微管蛋白干扰分子与抑制核内复制的药物（例如 Pifithrin-α）相结合可能有助于抑制 OPC/神经胶质瘤的生长并限制耐药性。

The abnormal growth of oligodendrocyte precursor cells (OPCs) significantly contributes to the progression of glioblastoma tumors. Hence, molecules that block OPC growth may be of therapeutic importance in treating gliomas. 2-Methoxyestradiol (2ME), an endogenous tubulin-interacting metabolite of estradiol, is effective against multiple proliferative disorders. Based on its anti-carcinogenic and anti-angiogenic actions, it is undergoing phase II clinical trials. We hypothesize that 2ME may prevent glioma growth by targeting OPC growth. Here, we tested this hypothesis by assessing the impact of 2ME on the growth of an OPC line, "Oli-neu", and dissected the underlying mechanism(s). Treatment with 2ME inhibited OPC growth in a concentration-dependent manner, accompanied by significant upregulation in the expression of p21 and p27, which are negative cell-cycle regulators. Moreover, treatment with 2ME altered OPC morphology from multi-arm processes to rounded cells. At concentrations of 1uM and greater, 2ME induced apoptosis, with increased expressions of caspase 3, PARP, and caspase-7 fragments, externalized phosphatidylserine staining/APOPercentage, and increased mitochondrial activity. Flow cytometry and microscopic analysis demonstrated that 2ME triggers endoreduplication in a concentration-dependent fashion. Importantly, 2ME induced cyclin E, JNK1/2, and p53 expression, as well as OPC fusion, which are key mechanisms driving endoreduplication and whole-genome duplication. Importantly, the inhibition of p53 with pifithrin-α rescued 2ME-induced endoreduplication. The pro-apoptotic and endoreduplication actions of 2ME were accompanied by the upregulation of survivin, cyclin A, Cyclin B, Cyclin D2, and ppRB. Similar growth inhibitory, apoptotic, and endoreduplication effects of 2ME were observed in CG4 cells. Taken together, our findings provide evidence that 2ME not only inhibits OPC growth and triggers apoptosis, but also activates OPCs into survival (fight or flight) mode, leading to endoreduplication. This inherent survival characteristic of OPCs may, in part, be responsible for drug resistance in gliomas, as observed for many tubulin-interacting drugs. Importantly, the fate of OPCs after 2ME treatment may depend on the cell-cycle status of individual cells. Combining tubulin-interfering molecules with drugs such as pifithrin-α that inhibit endoreduplication may help inhibit OPC/glioma growth and limit drug resistance.