乳腺癌化疗耐药性阻碍化疗疗效；研究人员研究天然产物的药理活性，寻找潜在的解决方案。本研究旨在确定桑色素（一种从 Maclura pomifera 中分离出的生物类黄酮）对两种 Dox 抗性人乳腺癌细胞系 MDA-MB-231 (MDA-DR) 和 MCF-7 (MCF-DR) 的影响。 Sulforhodamine B 和集落形成试验证明了桑色素对两种细胞系的细胞毒性作用。桑色素诱导 DNA 损伤并降低 DNA 修复机制，这是化学抗性的一个特征。此外，桑色素还能降低细胞周期调节因子的蛋白表达，例如细胞周期蛋白 D1、CDK4、细胞周期蛋白 E1、细胞周期蛋白 B1 和 p-Rb，从而阻止细胞周期进程。此外，桑色素略微降低了 PARP 和 Bcl-xL 的表达，但使 LC3-II 和 RIPK3 的表达保持不变。膜联蛋白-V/7-AAD 分析显示桑色素分别增加了 MDA-DR 和 MCF-DR 细胞中的 7-AAD 阳性细胞和膜联蛋白-V 阳性细胞。此外，桑色素可增加 p-AMPK 和 p-LKB1 水平；因此，抑制 mTOR 途径的磷酸化，但通过诱导溶酶体降解降低 t-AMPK 水平，并且 AMPK 激活剂 AICAR 降低了 Raptor、细胞周期蛋白 D1、CDK4、细胞周期蛋白 E1 和磷酸化以及总 mTOR 水平，表明 AMPK诱导细胞死亡的关键角色。此外，桑色素调节 MAPK 磷酸化并减弱 p-Akt 和 p-GSK3αβ 水平；从而抑制细胞存活。此外，桑色素抑制了我们的 MDA-DR 异种移植小鼠模型中的肿瘤生长。这些发现表明桑色素是治疗 Dox 耐药性乳腺癌的潜在疗法，它通过诱导 DNA 损伤和调节 LKB1/AMPK/mTORC1 通路，以及调节 MAPK 和 Akt/GSK3αβ 信号通路来实现这一点。© 2024 International生物化学与分子生物学联盟。

Breast cancer chemoresistance hampers chemotherapy efficacy; researchers investigate the pharmacological activities of natural products for potential solutions. This study aimed to determine the effect of morin, a bioflavonoid isolated from Maclura pomifera, on two Dox-resistant human breast cancer cell lines MDA-MB-231 (MDA-DR) and MCF-7 (MCF-DR). Sulforhodamine B and colony-forming assays demonstrated the cytotoxic effect of morin on both cell lines. Morin induced DNA damage and reduced the DNA repair mechanism, a feature of chemoresistance. In addition, morin reduced the protein expressions of cell cycle regulators, such as cyclin D1, CDK4, cyclin E1, cyclin B1, and p-Rb, thereby halting cell cycle progression. Moreover, morin slightly reduced PARP and Bcl-xL expressions but left LC3-II and RIPK3 expressions unchanged. Annexin-V/7-AAD analysis showed morin increased 7-AAD positive cells and annexin-V positive cells among MDA-DR and MCF-DR cells, respectively. In addition, morin increased p-AMPK and p-LKB1 levels; and, thus, inhibited phosphorylation of the mTOR pathway, but decreased t-AMPK levels by inducing lysosomal degradation, and AICAR, an AMPK activator, reduced Raptor, cyclin D1, CDK4, cyclin E1 and phosphorylated, and total mTOR levels, indicating AMPK is a key player in inducing cell death. Also, morin modulated MAPK phosphorylation and attenuated p-Akt and p-GSK3αβ levels; and thus, inhibited cell survival. In addition, morin suppressed tumor growth in our MDA-DR xenografted mouse model. These findings indicate that morin is a potential treatment for Dox-resistant breast cancer and that it does so by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 pathway, along with regulating the MAPK, and Akt/GSK3αβ signaling pathways.© 2024 International Union of Biochemistry and Molecular Biology.