A Bibenzyl from Dendrobium pachyglossum Exhibits Potent Anti-Cancer Activity Against Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from <i>Dendrobium</i> species, particularly bibenzyl derivatives, possess diverse pharmacological activities, yet their potential against GBM remains largely unexplored. Here, we investigated the anticancer activity of 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (TDB), a potent antioxidant bibenzyl derivative isolated from <i>Dendrobium pachyglossum</i>. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis <i>via</i> Bax upregulation and Bcl-xL/Mcl-1 downregulation, and inhibited both mTORC1 and mTORC2 signaling. TDB also impaired cell migration and downregulated epithelial-mesenchymal transition (EMT)-associated proteins. Notably, TDB enhanced the cytotoxicity of temozolomide (TMZ), the current standard of care for GBM. These TMZ-sensitizing properties were further confirmed in patient-derived xenograft (PDX) Jx22 cells. To assess its potential for central nervous system delivery, blood-brain barrier (BBB) permeability was predicted using four independent <i>in silico</i> platforms-ADMETlab 3.0, LogBB_Pred, LightBBB, and BBB Predictor (Tree2C)-all of which consistently classified TDB as BBB-permeable. This predicted CNS accessibility, together with its potent anticancer profile, underscores TDB's translational promise. Collectively, our findings identify TDB as a plant-derived antioxidant with multifaceted anti-GBM activity and favorable BBB penetration potential, warranting further <i>in vivo</i> validation and preclinical development as a novel therapeutic candidate for GBM.