Medical School, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials for Ministry of Education, Nankai University, Tianjin 300071, China.
College of Mathematics, Nankai University, Tianjin 300071, China.
Brain Res. 2018 Nov 15;1699:1-8. doi: 10.1016/j.brainres.2018.06.026. Epub 2018 Jun 20.
High-grade gliomas (HGGs; grades III and IV) are the most common and aggressive adult primary brain tumors, and their invasive nature ranks them the fourth in the incidence of cancer death. In our previous study, we found that AG-1031 and AG-1503 showed inhibitory effects on several cancer cell lines. In this study, C6 glioma-bearing rats were treated with AG-1031 or AG-1503. Western blot results of autophagy-associated protein (LC3 II/I, Beclin-1) and apoptosis-associated proteins (caspase-3, Bcl-2, Bax) revealed that AG-1031 could activate apoptotic signal pathway via inhibiting autophagy process in cancer cells. HE staining indicated that the tumor volumes were significantly decreased in AG-1031 and AG-1503 treated rats compared to non-treated C6 glioma-bearing rats. Meanwhile, AG-1031 and AG-1503 significantly decreased the expression of VEGF, a marker of invasion ability of tumor, in tumor tissue. The novel object recognition test showed that cognitive functions in C6 glioma-bearing rats were considerably damaged, whereas AG-1031 and AG-1503 significantly impeded the cognitive impairment. AG-1031 and AG-1503 efficiently alleviated the glioma-induced impairments of long-term potentiation (LTP), which was damaged in C6 glioma-bearing rats. Furthermore, AG-1031 and AG-1503 augmented the expression of synaptophysin (SYP), which were decreased in glioma rats. In conclusion, our results suggest that AG-1031 and AG-1503 can inhibit the expansion of glioma, and improve the cognitive impairment caused by glioma in glioma-bearing rats.
高级别神经胶质瘤（HGG；III 级和 IV 级）是最常见且侵袭性最强的成人原发性脑肿瘤，其侵袭性使其在癌症死亡发病率中排名第四。在我们之前的研究中，我们发现 AG-1031 和 AG-1503 对几种癌细胞系具有抑制作用。在这项研究中，我们用 AG-1031 或 AG-1503 治疗 C6 神经胶质瘤荷瘤大鼠。自噬相关蛋白（LC3 II/I、Beclin-1）和凋亡相关蛋白（caspase-3、Bcl-2、Bax）的 Western blot 结果表明，AG-1031 通过抑制癌细胞的自噬过程激活凋亡信号通路。HE 染色表明，与未经处理的 C6 神经胶质瘤荷瘤大鼠相比，AG-1031 和 AG-1503 处理的大鼠的肿瘤体积明显减小。同时，AG-1031 和 AG-1503 显著降低了肿瘤组织中血管内皮生长因子（VEGF）的表达，VEGF 是肿瘤侵袭能力的标志物。新物体识别测试表明，C6 神经胶质瘤荷瘤大鼠的认知功能受到严重损害，而 AG-1031 和 AG-1503 显著阻碍了认知障碍的发生。AG-1031 和 AG-1503 有效地缓解了 C6 神经胶质瘤荷瘤大鼠受损的长时程增强（LTP）。此外，AG-1031 和 AG-1503 增加了突触小体蛋白（SYP）的表达，SYP 在神经胶质瘤大鼠中表达降低。总之，我们的结果表明，AG-1031 和 AG-1503 可以抑制神经胶质瘤的扩张，并改善神经胶质瘤荷瘤大鼠的认知障碍。
