Natural Flavonoids Genistein and Baicalein as Well-Tolerated Radiosensitizers to Enhance the Efficacy of 177Lu-PSMA617 in Prostate Cancer: In Vitro and In Vivo Studies

The efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) is limited by tumor heterogeneity and intrinsic radioresistance. This study investigates two natural flavonoids, genistein and baicalein, as potential radiosensitizers to improve the therapeutic effectiveness of 177Lu-PSMA617 therapy. In vitro, combined treatment with low-toxicity concentrations (5-15 μM, based on cellular IC50 of either flavonoid dose-dependently enhanced the cytotoxicity of 177Lu-PSMA617 against the human prostate cancer cell line LNCaP, reducing its IC50 to 14.2%-45.1% of that with monotherapy. All combination regimens demonstrated synergistic interaction, with combination indices (CI) below 0.82. Mechanistically, the combinations (particularly at 10 μM) induced a pro oxidant shift (increasing ROS by 78%-144%), amplified DNA damage (γ-H2AX increased by 85-115%), and promoted apoptosis (Caspase-3 activity increased by 325-389%) while suppressing pro-survival p-AKT. Transcriptomic profiling further revealed that both flavonoids induced a pro apoptotic gene signature and significantly modulated multiple cancer-related pathways, particularly inhibiting key DNA double-strand break repair pathways such as non-homologous end-joining (NHEJ) . In vivo, combination therapies profoundly inhibited tumor growth (50.2-78.1% reduction vs. monotherapy) and extended survival, with no overt systemic toxicity observed in this preliminary assessment. This work establishes genistein and baicalein as effective, multi-targeted radiosensitizers that enhance 177Lu-PSMA617 efficacy by cooperatively amplifying DNA damage, inhibiting repair mechanisms, and activating the apoptotic cascade. Their natural origin and established safety profile, coupled with their natural origin and established safety profile, underscore their translational potential. Thus, genistein and baicalein represent promising novel adjuvants for prostate cancer radioligand therapy.