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

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.

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 γ-H2AX foci and p-ATM levels.

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.

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.