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Background: Glioblastoma (GBM) is a very frequent primary tumour in the cerebrospinal nervous system. Temozolomide (TMZ) is the first-line treatment for patients with GBM. However, some of GBM patients do not respond to TMZ. O6-methylguanine-DNA-methytransferase (MGMT) remains a major cause. In a previous study, we detected antibodies against MGMT peptides in patients with glioma, and five highly responsive autoantibodies anti-MGMT-02, anti-MGMT-04, anti-MGMT-07, anti-MGMT-10, and anti-MGMT-18 were identified that could be used to dynamically assess chemotherapy-resistant TMZ. Therefore, targeting MGMT peptides may be a potential therapeutic approach for GBM to fight TMZ resistance. Methods: First, MGMT-02 and MGMT-04 polypeptides with cell-penetrating peptides were designed and connected to FITC tracer for immunofluorescence localisation. CCK-8 and colony formation assay were performed to evaluate cell proliferation ability. Western blot and immunofluorescence analysis were used to detected the expression of apoptosis-related protein. Flow cytometry was used to detect the proportion of apoptosis in cells. TMZ-resistant effect of MGMT-02/04 peptides was assessed in intracranial xenograft nude mouse model. Results: We also found reduced apoptosis of cells treated with MGMT-02 and MGMT-04 peptides and TMZ compared with those treated separately with TMZ in vivo and in vitro experiences. Conclusion: The results of this study indicate that MGMT-02 and MGMT-04 peptides have a role in glioma resistance and that MGMT peptides may serve as a precise target for TMZ-resistant GBM.