Raddeanin A is associated with enhanced anti-tumor efficacy of doxorubicin in a murine breast cancer model by modulating MDR1 expression

Background Doxorubicin (DOX) efficacy in breast cancer is limited by multidrug resistance (MDR) associated with P-gp/MDR1. Raddeanin A (RA) shows antitumor potential, but its role in modulating MDR is unexplored. Purpose To evaluate whether RA may potentiate DOX anticancer effects and to examine potential mechanisms potentially involving MDR1-associated efflux. Methods Synergy was assessed in 4T1 cells (MTT, colony formation, apoptosis, ROS, Nrf2/HO-1). Molecular docking and flow cytometry evaluated RA-MDR1 interaction and DOX accumulation. In vivo efficacy and cardiotoxicity were examined in a 4T1 xenograft model. Results RA was associated with DOX sensitivity (reduced IC 50 ), synergistically suppressed proliferation, increased ROS/apoptosis, and was associated with downregulation of Nrf2/HO-1 expression levels. Mechanistically, RA was associated with reduced MDR1 expression and increased intracellular DOX accumulation, consistent with the possibility that RA may be associated with altered drug retention potentially related to MDR1. In vivo , RA + DOX combination was associated with improved tumor inhibition without additional systemic or cardiotoxicity (normal body weight, cardiac histology, CK/CK-MB). This was associated with enhanced apoptosis and reduced MDR1 expression, along with findings consistent with reduced Nrf2/HO-1 expression levels in tumors. Conclusion Our findings suggest that RA may be associated with reduced MDR1 expression and increased intracellular DOX accumulation, increased apoptotic signaling, and downregulation of Nrf2/HO-1 expression levels, as suggested by correlative and pharmacological data. These observations are consistent with the possibility that RA may serve as a potential adjuvant to improve DOX efficacy in breast cancer, although further mechanistic studies are required to establish causality.