20(S)-protopanaxadiol enhances temozolomide responsiveness in MGMT-expressing glioblastoma: Wnt/β-catenin attenuation and MGMT downregulation.

Background: Glioblastoma is a highly aggressive primary brain malignancy, and O Methods: U87, U251, LN18, and T98G glioblastoma cells were studied, with combination and mechanistic analyses focused on MGMT-expressing LN18 and T98G cells. Network pharmacology was used to prioritize candidate targets and pathways, followed by experimental evaluation using cell viability, apoptosis, migration, invasion, comet assays, western blotting, and immunofluorescence assays. Preclinical Results: 20(S)-PPD reduced viability in all four cell lines and promoted apoptosis while decreasing migration- and invasion-related phenotypes in LN18 and T98G cells. Combined treatment produced greater inhibitory effects than either monotherapy and enhanced TMZ-induced DNA damage. Network pharmacology prioritized Wnt signaling as a candidate pathway. Subsequent cellular and Conclusion: 20(S)-PPD enhanced TMZ responsiveness in MGMT-expressing glioblastoma models, and this effect was associated with attenuated Wnt/β-catenin signaling and reduced MGMT expression. Acquired TMZ-resistant derivatives and patient-derived resistant models were not examined; therefore, the conclusions are limited to the models evaluated here. These findings provide preclinical evidence supporting further evaluation of 20(S)-PPD as a potential TMZ chemosensitizer.