Therapeutic Potential of Tetrandrine Compared to Temozolomide in Treating Glioblastoma Multiforme Under Normoxic and Hypoxic Conditions

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. Necrosis, and by inference hypoxia, is a pathognomonic feature of GBM tumors, where hypoxia significantly contributes to chemoresistance, leading to local treatment failure and disease progression. Although temozolomide (TMZ) is the main treatment option, 60–75% of GBM patients do not benefit from it. This study aimed to evaluate the therapeutic potential of Tetrandrine (TET) in combination with or compared to TMZ in treating GBM cells (M010b and U87) under both normoxic and hypoxic conditions. The therapeutic potential was assessed using qRT-PCR, MTT assay, combination index analysis, flow cytometry for apoptosis and cell cycle analysis, scratch assay, gelatin zymography, measurement of mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) production, and molecular docking. Under both normoxic and hypoxic conditions, TET showed significant cytotoxicity in both cell lines compared to TMZ. A synergistic effect was observed only under normoxia at 2× IC50 concentrations in M010b cells, and at 4× IC50 concentrations in U87 cells. TET significantly increased the sub-G1 cell population and apoptosis compared to TMZ in both cell lines under normoxic and hypoxic conditions, while TMZ induced G2/M arrest in U87 cells under both conditions. TET significantly increased ROS production in both cell lines under normoxia. Under both conditions, ΔΨm was significantly reduced by TET in M010b cells and by TMZ in both cell lines. TET and TMZ significantly reduced pro-MMP-2 levels in M010b cells under both conditions and in U87 cells under normoxia. In conclusion, given the limited therapeutic potential of TMZ, our findings suggest that TET could be a viable alternative treatment option for GBM.