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

## TL;DR

A natural compound from a Dendrobium orchid shows strong anti-cancer effects against a deadly brain tumor and can cross the blood-brain barrier.

## Contribution

Identifies a bibenzyl compound with potent anti-glioblastoma activity and BBB permeability, offering a novel therapeutic candidate.

## Key findings

- TDB reduced cancer cell viability, suppressed growth, and induced apoptosis in U87MG cells.
- TDB inhibited mTORC1 and mTORC2 signaling and enhanced temozolomide's effectiveness in GBM cells.
- In silico analysis confirmed TDB's potential to cross the blood-brain barrier.

## Abstract

Glioblastoma 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.