Abstract

The efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy in metastatic castration-resistant prostate cancer is limited by tumor heterogeneity and intrinsic radioresistance. This study investigates 2 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 to 15 μM), based on cellular median inhibitory concentration (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% to 45.1% of that with monotherapy. All combination regimens demonstrated synergistic interaction, with combination indices below 0.82. Mechanistically, the combinations (particularly at 10 μM) induced a pro-oxidant shift (increasing reactive oxygen species by 78% to 144%), amplified DNA damage (γ-H2AX increased by 85% to 115%), and promoted apoptosis (caspase-3 activity increased by 325% to 389%) while suppressing prosurvival p-AKT. Transcriptomic profiling further revealed that both flavonoids induced a pro-apoptotic gene signature and markedly modulated multiple cancer-related pathways, particularly inhibiting key DNA double-strand break repair pathways such as nonhomologous end-joining. In vivo, combination therapies profoundly inhibited tumor growth (50.2% to 78.1% reduction versus 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 underscore their translational potential.