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

Ruihua Wu,1 Amirabas Bostani,2 Junmei Wang3 1Department of Obstetrics and Gynecology, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an, 710000, People’s Republic of China; 2Department of Biology, Science & Research Institute, Islamic Azad University, Tehran, Iran; 3Department of Obstetrics and Gynecology, XD Group Hospital, Xi’an, 710000, People’s Republic of ChinaCorrespondence: Junmei Wang, Department of Obstetrics and Gynecology, XD Group Hospital, Xi’an, 710000, People’s Republic of China, Tel +86 3319206720, Email [email protected]: 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< 0.001) without systemic toxicity (stable body weight).Conclusion: Morin synergizes with DOX by modulating apoptosis, autophagy, cell cycle, and oxidative stress, overcoming chemoresistance while reducing toxicity. These findings position morin as a promising, orally bioavailable adjunct worthy of further clinical investigation for optimizing DOX therapy in refractory EOC.Keywords: ovarian neoplasms, flavonoids, drug resistance, apoptosis, autophagy, xenograft model antitumor assays