The nanoprodrug of polytemozolomide combines with MGMT siRNA to enhance the effect of temozolomide in glioma

Abstract

Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.

Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions

“…The efficacy of targeted modulation of signalling pathways was compared in two GB cell lines, U-251 MG and T98-G. These cell lines differ in expression levels of O6-methylguanine-DNA methyltransferase (MGMT), which contributes to the resistance of cells to drugs that act via DNA alkylation: U-251 MG expresses low levels of MGMT, while T98-G expresses higher levels of MGMT and is more resistant to alkylating agents 13 . We found that among the choice of screened compounds, the inhibitors of Aurora family possessed the highest potency.…”

Ceruloplasmin is associated with the infiltration of immune cells and acts as a prognostic biomarker in patients suffering from glioma

“…Glioma is the most commonly occurring and malignant adult brain tumor ( Xu et al, 2023 ), and divided into ependymoma, astrocytoma [including glioblastomas (GBM)], oligodendroglioma, mixed glioma, and a few other tumors that vary widely in histology (from benign ependymoma to the most aggressive and lethal grade-IV GBM) ( Antin et al, 2020 ; Walsh et al, 2023 ). Despite multiple conventional therapy, including surgical resection, chemoradiotherapy and immunotherapy, glioma still possess a high recurrence and fatality rate ( Dong et al, 2023 ).…”