Molecular targeted therapy focusing invasion signaling in malignant glioma cell

我们评估了使用临床可用的选择性小分子抑制剂抑制Notch和Akt在胶质瘤中的治疗可能性。此外，我们研究了胶质母细胞瘤（GBM）细胞通过抑制gsk3 β对替莫唑胺（TMZ）增敏的分子机制。Notch和Akt抑制剂以剂量依赖的方式显著抑制细胞生长、迁移和侵袭。然而，在增殖实验中，联合治疗的效果并不超过Akt抑制剂单药治疗。抑制侵袭，进一步增强联合治疗。因此，联合治疗可能对抑制侵袭有效，但对抑制增殖无效。抑制gsk3 β增强TMZ效应。c-Myc与MGMT启动子结合，随后募集DNMT3A，调节MGMT启动子甲基化水平。因此，gsk3 β抑制通过c- myc介导的启动子甲基化沉默MGMT表达，从而增强TMZ效应。

We assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors. Additionally, we investigated the molecular mechanisms of sensitization of glioblastoma (GBM) cells to temozolomide (TMZ) by GSK3beta inhibition. Notch and Akt inhibitors significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. However, the effect of combination treatment did not exceed that of Akt inhibitor monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy. Therefore, combination therapy may be effective for inhibiting invasion but not proliferation. GSK3beta inhibition enhanced TMZ effect. c-Myc binds to the MGMT promoter with consequent recruitment of DNMT3A, regulating the levels of MGMT promoter methylation. Therefore, GSK3beta inhibition enhances TMZ effect by silencing MGMT expression via c-Myc-mediated promoter methylation.