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

  • Research (Wash D C). 2026 Jun 10:9:1314. doi: 10.34133/research.1314.
Congjie He  1 ,  Yuting Shao  1 ,  Ying Bao  2 ,  Jicong Li  2 ,  Hongwei Si  3 ,  Jian He  1  4
Affiliations
  • 1. Department of Nuclear Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 2. Beijing Atomic Energy Institute, Beijing, China.
  • 3. Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4. Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Nanjing, China.
PMID: 42281770 DOI: 10.34133/research.1314
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. Thus, genistein and baicalein represent promising novel adjuvants for prostate Cancer radioligand therapy.

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