Differential regulation of radioadaptation by quercetin between human normal and cancer cells

Objective: Radiotherapy is a primary treatment for many cancers, but its efficacy is often limited by collateral damage to healthy tissues. Radioadaptation, a phenomenon where low-dose radiotherapy (LDRT) enhances a cell's ability to withstand subsequent high-dose radiation, occurs in normal cells but is generally absent in cancer cells. Quercetin, a natural flavonoid with antioxidant and anticancer properties, has been proposed as a potential radiomodulator. This study aimed to investigate whether quercetin could differentially regulate the radioadaptive response in human normal breast epithelial versus breast cancer cells. Methods: Cell viability, clonogenic survival, oxidative stress, and DNA damage responses were assessed in MCF10A and MCF7 cells following treatment with LDRT (0.1 Gy), quercetin, and high-dose radiation. NQO1 and NRF2 expression levels were measured using RT-qPCR, Western blotting, and immunofluorescence. DNA damage was evaluated by ?-H2AX foci and p-ATM levels. Results: In MCF10A cells, LDRT pre-treatment enhanced resistance to subsequent radiation, which was further potentiated by quercetin, as shown by increased cell viability (p = 0.007), increased surviving fraction (enhancement ratio = 0.85, at 10 % surviving fraction), enhanced adaptation at 4 h on NQO1 mRNA (p < 0.01) and protein expression (p < 0.01), with a modest effect at 24 h on NQO1 mRNA (p = 0.890) and protein (p = 0.453) and reduced ROS level at 24 h (p = 0.021). Quercetin promoted NRF2 delocalization (p = 0.005). In contrast, MCF7 cells showed no radioadaptive response, and quercetin even increased radiosensitivity (enhancement ratio of surviving fraction = 1.12, at 10 surviving fraction) by maintaining ROS levels and DNA damage. Conclusion: Quercetin selectively enhances radioadaptation in normal cells by activating antioxidant pathways and reducing DNA damage, while preserving or amplifying radiosensitivity in cancer cells. These findings support quercetin may serve as a potential radiomodulating agent with favorable safety for increasing the therapeutic window of radiotherapy.