School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing 210094, China.
State Key Laboratory of Marine Resource Utilization in South China Sea, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
Molecules. 2022 May 25;27(11):3399. doi: 10.3390/molecules27113399.
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.
乳腺癌是全球女性癌症死亡的主要原因，其发病率和死亡率逐年上升。表阿霉素（EPI）是治疗乳腺癌的常用药物，但由于剂量累积，不幸的是会导致患者心脏毒性。因此，迫切需要新的治疗方法来提高乳腺癌细胞对 EPI 的敏感性。在这项研究中，我们发现熊果酸（UA）可以显著提高人乳腺癌 MCF-7/MDA-MB-231 细胞对 EPI 的药物敏感性。接下来，我们观察到 UA 和 EPI 的联合治疗可以上调自噬相关蛋白 Beclin-1、LC3-II/LC3-I、Atg5 和 Atg7 的表达，并降低 PI3K 和 AKT 的表达水平，这表明潜在的机制应该通过调节 III 类 PI3K(VPS34)/Beclin-1 途径和 PI3K/AKT/mTOR 途径来实现。此外，我们发现自噬抑制剂 3-甲基腺嘌呤（3-MA）可以显著逆转 UA 和 EPI 联合处理对 MCF-7 和 MDA-MB-231 细胞的抑制作用。这些发现表明，UA 通过调节自噬途径可以显著提高 MCF-7 和 MDA-MB-231 细胞对 EPI 的敏感性。我们的研究可能为联合治疗提供新的治疗策略。
