Aung H.M.Wattanathamsan O.Sanookpan K.Hongprasit A.Muangnoi C.Phumsuay R.Rojpitikul T.Sritularak B.Bunlue T.Chantaravisoot N.Oliva C.R.Griguer C.E.Buranasudja V.Mahidol University2025-11-082025-11-082025-10-01Antioxidants Vol.14 No.10 (2025)https://repository.li.mahidol.ac.th/handle/123456789/112974Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and a poor prognosis. Natural phytochemicals from Dendrobium 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 Dendrobium pachyglossum. In U87MG cells, TDB reduced viability in a dose- and time-dependent manner, suppressed clonogenic growth, induced apoptosis via 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 in silico 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 in vivo validation and preclinical development as a novel therapeutic candidate for GBM.Biochemistry, Genetics and Molecular BiologyAgricultural and Biological SciencesArticleSCOPUS10.3390/antiox141012122-s2.0-10502020288020763921