Beta‐Caryophyllene Augments Radiotherapy Efficacy in <scp>GBM</scp> by Modulating Cell Apoptosis and <scp>DNA</scp> Damage Repair via <scp>PPARγ</scp> and <scp>NF</scp> ‐ <scp>κB</scp> Pathways

Glioblastoma multiforme (GBM) is a highly aggressive brain malignancy with limited treatment options. Radiotherapy (RT) is often used for treating unresectable GBM; however, the outcomes are often limited due to the radioresistance of GBM. Therefore, the discovery of potential radiosensitizers to enhance GBM responses to RT is crucial. Beta-caryophyllene (BCP), a natural cannabinoid, promotes cancer apoptosis by upregulating the PPARγ signaling pathway and can cross the blood-brain barrier due to its lipophilic nature. This study aimed to evaluate the radiosensitizing potential of BCP in GBM cells. U87MG and GL261 cells and a GL261 tumor-bearing model were treated with RT, BCP, or both. Treatment efficacy was assessed using the MTT assay and tumor growth tracking, and the underlying mechanisms were investigated using western blotting, immunofluorescence staining, and other analyses. BCP synergistically enhanced the efficacy of RT in cell culture, as evidenced by the combination index determined through the MTT assay. This enhancement was mediated by the BCP-induced deceleration of DNA damage repair, as demonstrated by sustained γH2AX signal, upregulated PPARγ levels, and reduced expression of pAKT, pERK, and NF-κB, indicating apoptosis induction and inhibition of survival pathways. BCP significantly inhibited tumor growth in GL261 tumor-bearing mice with no discernible side effects. These findings indicate that BCP may serve as a potential radiosensitizer for improving RT outcomes in GBM by inhibiting DNA repair, inducing apoptosis, and suppressing anti-apoptotic and survival pathways.