Morin overcomes doxorubicin resistance in human breast cancer by inducing DNA damage and modulating the LKB1/AMPK/mTORC1 signaling pathway

Abstract 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.