monoHER as a selective radiosensitizer in breast cancer

Background: Radiotherapy is one of the standard treatments for breast cancer, but its efficacy is limited by tumour radioresistance and damage to surrounding normal tissues. In recent years, combining different therapeutic modalities has improved treatment efficacy while minimizing adverse effects. Flavonoids, abundant in many traditional Chineses medicines, have demonstrated both radioprotective and radiosensitizing properties. MonoHER, the flavonoid derivative of interest, has shown anticancer potential; however, its role in radiosensitization has not been investigated. Here, we determined in vitro the radiosensitizing properties of monoHER in breast cancer and normal mammary cells and investigated its potential mechanism.

Methods: Breast cancer cells with different p53 status (MCF7, wild-type; T47D, mutant) and normal mammary cells (MCF10A, p53 wild-type) were treated with monoHER and radiation. Cell viability, clonogenic survival, apoptosis, and DNA damage marker (γ-H2AX foci) were assessed. Western blotting examined ATM/p53 signalling. Interaction of monoHER with p53 was analysed by molecular docking and CETSA.

Results: MonoHER selectively enhanced radiation-induced cytotoxicity in MCF7 (p<0.01) cells and in T47D (p<0.05) but had protective effects in MCF10A (p<0.01) cells. Combined treatment increased apoptosis (p<0.001) and DNA damage (p=0.045) in MCF7 cells, accompanied by upregulation of p-ATM (p=0.011), p-p53 (p=0.023), and total p53 (p=0.026), while in T47D cells, no significant differences have been observed. Docking and CETSA confirmed direct binding of monoHER to wild-type p53, increasing its thermal stability. MonoHER alone showed minimal cytotoxicity, suggesting a priming rather than direct killing effect.

Conclusion: This study demonstrates that monoHER selectively enhances the radiosensitivity of breast cancer cells in a p53-dependent manner. MonoHER amplified radiation-induced DNA damage, activated the ATM/p53 pathway, and promoted apoptosis in MCF7 cells with wild-type p53, whereas it had little effect in T47D (mutant p53) or protective effect in normal MCF10A cells. These findings provide mechanistic insight into the radiosensitizing activity of monoHER and support its potential application in combination with radiotherapy for the treatment of p53-wild-type breast cancer.

Chujie Li, a PhD student at Maastricht University in the Netherlands, specializes in anticancer pharmacology. Her research focuses on the development and evaluation of novel therapeutic agents in cancer treatment, particularly in combination strategies. Her recent studies explored strategies to widen the radiotherapy therapeutic window, with the aim of sensitizing tumors to treatment while preventing radiation-induced damage to normal tissues.