Study On The Enhancement Of Radiosensitivity Of Human Glioblastoma Subcutaneous Xenograft In Nude Mice By Inhibiting GSK3?

Glioblastoma multiforme(GBM)is a tumor of the central nervous system and has the characteristics of low survival rate,high degree of malignancy,high recurrence rate,and high invasiveness.Due to the invasive growth of GBM,it is difficult to completely remove the GBM.Currently,the most effective clinical treatment is surgical resection of the tumor combined radiotherapy.However,due to the existence of radiotherapy resistance,tumors in most patients still relapse.The radiotherapy resistance of GBM has a close relationship with the activation of DNA double strand breaks(DSBs).Previous studies have shown that cytoplasmic protein Glycogen synthase kinase 3?(GSK3?)translocates into the nucleus under the action of ionizing radiation.After GSK3? transfers to nucleus,it will bind to p53 binding protein(53BP1)and induce its phosphorylation,in turn,promotes the repair process of DSBs in U87 cells,which increases the radiotherapy resistance of tumors,and leads to decreased apoptosis and increased cell proliferation rate.Since the previous experiments were all in vitro experiments,it is necessary to further investigate whether inhibiting the expression of GSK3? can eliminate nuclear translocation of GSK3? and inhibit its involvement in 53BP1-mediated DSBs repair in vivo by constructing tumor-bearing mouse models.And it can provide a scientific basis for the development of radiosensitizers targeting GSK3? at the tissue and animal level.U87 cells were inoculated nude mice to establish glioma xenograft model,were randomly divided into 4 groups: 1)control group: without any treatment;2)IR group: received 25 Gy ionizing radiation therapy;3)SB216763 group: 5mg / kg SB216763 intraperitoneal injection;4)SB216763 + IR group: 5mg / kg SB216763 intraperitoneal injection and 25 Gy ionizing radiation.Observe and record the tumor volumes change and weights change of tumor-bearing mouse in each group within 20 days and the 100-day survival rate were also recorded.Mouse subcutaneous tumors were stripped,weighed and fixed for TUNEL staining.The results showed compared with IR treated group?SB216763 treated group and saline control group,that tumor volume and tumor weight were significantly decreased in SB216763 + IR treated group(n = 10,P <0.05 by ANOVA with Bonferroni post-hoc test).The survival time of SB216763 + IR treated group was significantly longer than that other groups(n = 10,0.05 by Kaplan-Meier).In addition,more apoptotic U87 cells were observed in the TUNEL-labeled SB216763 + IR treated group.Therefore,based on the above qualitative and quantitative analysis of the results,indicating that GSK3? inhibitor SB216763 can increase radiosensitivity of glioblastoma in vivo.