MonoHER selectively enhances the radiotherapy response in p53 wild-type breast cancer via stabilization of p53

Background: Radiotherapy is one of the standard treatments for breast cancer, but its efficacy is limited by tumour radioresistance. Radiosensitizers can improve treatment outcomes. MonoHER, a flavonoid derivative, has shown anticancer potential; however, its role in radiosensitization has not been investigated. Here, we determined the radiosensitizing properties of monoHER in vitro in breast cancer and normal mammary cells. Methods: Breast cancer cells with different p53 status (MCF7, wild-type; T47D, mutant) and normal mammary cells (MCF10A) were treated with monoHER and radiation. Cell viability, clonogenic survival, apoptosis, and 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 cytostatic effects in MCF7 (p < 0.01) cells and in T47D (p < 0.05), but had protective effect 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 = 026), while in T47D and MCF10A cells, there is no significant difference. 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: MonoHER modestly sensitize only p53-proficient breast cancer cells to radiation by stabilizing and activating p53, highlighting its potential as an adjuvant radiosensitizer.