Revisiting brachytherapy: Balancing cell death and antioxidant defense in glioblastoma treatment

Brachytherapy (BT) is favored over external beam radiation therapy (EBRT) for certain tumors with modest ionizing damage. However, the biological effect of BT in glioblastoma remains uncertain. Thus, this study aimed to compare BT and EBRT in glioblastoma treatment.

BT cell culture templates ensured equal in vitro doses between BT and EBRT. The effects of EBRT and BT on GL261 glioblastoma cells were detected by CCK8 assay, colony formation assay, and flow cytometry. In addition, cellular reactive oxygen species (ROS) levels and mitochondrial membrane potential were measured. Western blotting was used to verify the mechanisms underlying regulated cell death, including apoptosis and ferroptosis. A GL261 xenograft model was also constructed for in vivo validation.

BT significantly reduced GL261 viability and proliferation while promoting apoptosis. It also significantly increased ROS levels and altered MMP. Moreover, BT upregulated the level of γ-H2AX (DNA damage), GPX4, SLC7A11 (antioxidant defense), and PTGS2 (ferroptosis marker), indicating BT-induced ferroptosis and an adaptive cellular antioxidant response. In xenografts, BT significantly inhibited tumor growth, decreased CD31 expression levels indicating impaired angiogenesis, and increased HIF-1α levels reflecting exacerbated tumor hypoxia.

BT effectively induces oxidative stress, DNA damage, and ferroptosis in glioblastoma. It also triggers a robust antioxidant defense response while influencing angiogenesis and the hypoxic tumor microenvironment.