Ursolic Acid Enhances the Sensitivity of MCF-7 and MDA-MB-231 Cells to Epirubicin by Modulating the Autophagy Pathway

Breast cancer is the leading cause of cancer death among women in the world, and its morbidity and mortality are increasing year by year. Epirubicin (EPI) is a commonly used drug for the treatment of breast cancer but unfortunately can cause cardiac toxicity in patients because of dose accumulation. Therefore, there is an urgent need for new therapies to enhance the sensitivity of breast cancer cells to EPI. In this study, we found ursolic acid (UA) can significantly improve the drug sensitivity of human breast cancer MCF-7/MDA-MB-231 cells to EPI. Next, we observed that the co-treatment of UA and EPI can up-regulate the expression of autophagy-related proteins Beclin-1, LC3-II/LC3-I, Atg5, and Atg7, and decrease the expression levels of PI3K and AKT, which indicates that the potential mechanism should be carried out by the regulating class III PI3K(VPS34)/Beclin-1 pathway and PI3K/AKT/mTOR pathway. Furthermore, we found the autophagy inhibitor 3-methyladenine (3-MA) could significantly reverse the inhibitory effect of co-treatment of UA and EPI on MCF-7 and MDA-MB-231 cells. These findings indicate that UA can dramatically enhance the sensitivity of MCF-7 and MDA-MB-231 cells to EPI by modulating the autophagy pathway. Our study may provide a new therapeutic strategy for combination therapy.