Magnolol Traverses the Blood-brain Barrier and Enhances Temozolomide-induced Intrinsic Apoptosis of Glioblastoma Cells via a p53 Redox Signaling Mechanism.

BACKGROUND/AIM: Temozolomide (TMZ) is the standard chemotherapeutic agent for glioblastoma multiforme (GBM), yet its efficacy is limited by severe side effects and high rates of drug resistance. This study investigated whether magnolol, a bioactive compound from Magnolia officinalis, enhances TMZ-induced apoptosis in glioblastoma cells and explored the underlying mechanisms.

MATERIALS AND

METHODS

The safety of magnolol was evaluated in normal human astrocytes and mouse cerebral endothelial cells (CECs). Its ability to traverse the CEC tight junction barrier was examined, followed by assessments of its effects on TMZ-induced apoptosis in human and mouse glioblastoma cells. Mechanistic studies focused on p53 redox signaling.

RESULTS

Magnolol at non-toxic concentrations crossed the CEC barrier and significantly potentiated TMZ-induced apoptosis in glioblastoma cells. Cotreatment decreased mitochondrial membrane potential, enhanced caspase-9 activity, and activated downstream caspases-3 and -6. Inhibition of caspase-9 or p53 phosphorylation attenuated magnolol's enhancement of TMZ-induced DNA fragmentation and apoptosis. Magnolol also elevated intracellular reactive oxygen species (ROS) levels, which further promoted p53 phosphorylation and apoptotic signaling. These synergistic effects were confirmed in both human U87MG and mouse GL261 glioblastoma cells.

CONCLUSION

Magnolol traverses the CEC barrier and amplifies TMZ-induced apoptosis in glioblastoma cells through an intrinsic ROS-p53-caspase signaling cascade. Given its safety toward normal astrocytes and endothelial cells, magnolol represents a promising adjuvant strategy to improve TMZ-based therapy, potentially mitigating drug resistance and adverse effects in GBM treatment.