18β-Glycyrrhetinic Acid Exerts Subgroup-Specific Antitumor Activity and Enhances Radiosensitivity in Medulloblastoma

Background: Radiotherapy (RT) is a cornerstone of medulloblastoma (MB) treatment, but its efficacy may be limited by intrinsic or acquired radioresistance, while radiation-related late effects remain a major concern in pediatric patients. 18β-Glycyrrhetinic acid (18β-GA), a bioactive triterpenoid derived from Glycyrrhiza glabra, has shown antitumor activity in several malignancies. This study evaluated its antitumor and radiosensitizing effects in biologically distinct MB models. Methods: DAOY cells, used as an SHH-associated, TP53-mutant model, and D283 cells, commonly considered a Group 3/Group 4-associated model, were treated with 18β-GA (2.5–5 μM), γ-radiation (2–4 Gy), or their combination. Cell viability, clonogenic survival and migration were assessed. Apoptosis was evaluated by caspase-3/7 activity and cleaved caspase-3 expression. Modulation of AMPK/NF-κB and SHH signaling was examined by immunoblotting and RT-qPCR. Results: 18β-GA reduced cell viability in a dose- and time-dependent manner and significantly reduced wound closure in DAOY cells and migratory capacity in D283 cells. D283 cells showed greater apoptotic sensitivity, accompanied by increased total and phosphorylated AMPK and reduced NF-κB p65 expression. In DAOY cells, 18β-GA reduced the expression of SHH-associated transcriptional markers, including GLI1, SOX2, CCND1, and MYC. Most importantly, 18β-GA significantly enhanced radiation response in both cell lines, producing greater reductions in viability and clonogenic survival than irradiation alone (p < 0.01). Combined treatment with 5 μM 18β-GA and 4 Gy reduced the surviving fraction to 0.013 in DAOY cells and approximately 0.01 in D283 cells (p < 0.001 versus radiation alone). This radiosensitizing effect was accompanied by increased caspase-3/7 activity and cleaved caspase-3 expression. Conclusions: 18β-GA exerts antitumor activity in biologically distinct MB models through differential modulation of SHH and AMPK/NF-κB signaling, while converging on enhanced apoptotic susceptibility and a profound loss of clonogenic survival after irradiation. These findings provide a strong rationale for further preclinical evaluation of 18β-GA as a potential radiosensitizing adjuvant in MB.