Synergistic Effects of Morin and Doxorubicin Overcome Chemoresistance in Ovarian Cancer: Preclinical Insights From in vitro and in vivo Models

Background: Epithelial ovarian cancer (EOC) remains highly lethal due to late-stage diagnosis and chemoresistance, necessitating strategies to enhance conventional therapies like doxorubicin (DOX) while mitigating toxicity. This study evaluated morin, a flavonoid, as an adjunct to DOX in chemoresistant EOC models. Methods: In vitro, DOX-resistant OVCAR-3-DR, OVCAR-3, and A2780 cells were treated with DOX, morin, or their combination. Synergy was assessed via MTT and apoptosis assays, alongside autophagy and cell cycle markers. In vivo, OVCAR-3-DR xenograft mice were divided into Sham, DOX (5 mg/kg), morin (15 and 30 mg/Kg), and combination groups. Tumor volume, apoptosis (BCL-2, caspase-3/9), autophagy (LC3, ATG5, Beclin-1), cell cycle regulators (Cyclin A2/D1), and oxidative stress (SOD, CAT, GPx, GR, GSH, MDA) were analyzed. Results: Findings demonstrated significant synergistic cytotoxicity, with a combination index (CI) of 0.72, and enhanced apoptosis. Combination therapy suppressed Cyclin A2/D1, upregulated autophagy markers (, and reduced oxidative stress. In vivo, DOX+Morin30 reduced tumor volume synergistically (p