Magnoflorine improves sensitivity to doxorubicin (DOX) of breast cancer cells via inducing apoptosis and autophagy through AKT/mTOR and p38 signaling pathways

Abstract

Breast cancer is a leading cause of cancer death among women worldwide. Doxorubicin (DOX) is a broad-spectrum anti-breast cancer agent, but its clinical use is restricted due to irreversible tissue toxicity. Thereby, new therapeutic approaches are urgently required to promote the sensitivity of breast cancer cells to DOX. Magnoflorine (Mag), a quaternary alkaloid isolated from Chinese herb Magnolia or Aristolochia, has various biological activities, such as anti-inflammation, anti-cancer, and anti-anxiety. In the study, we explored the effects Mag on the sensitivity of breast cancer cells to DOX. We demonstrated that Mag strongly promoted DOX-induced anti-proliferative effects in breast cancer cells while not in normal cells. Mag addition markedly promoted the effects of DOX on the inhibition of migration and invasion in breast cancer cells. DOX-triggered DNA damage in breast cancer cells was further accelerated by combination with Mag. DOX-induced cell distribution in G2/M phase was markedly elevated when co-treated with Mag. Additionally, DOX/Mag combinational treatment significantly induced apoptosis in breast cancer cells when compared to DOX alone group through inducing Caspase-3 cleavage. Moreover, Mag markedly promoted the role of DOX in autophagy induction by elevating light chain 3 (LC3)-II expression. Combination treatment with DOX and Mag significantly inhibited the activation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling, and promoted p38 mitogen-activated protein kinase (MAPK) pathway. In addition, treatment with wortmannin (Wor, a blocker of autophagosome formation) markedly reduced DOX/Mag-induced p38 MAPK activation and LC3 conversion in breast cancer cells. Further, in MCF-7 xenograft model, DOX combined with Mag displayed a significant anti-tumor effect with little toxicity to organs such as liver, heart, kidney and spleen. These findings suggested that Mag promoted the anti-cancer effects of DOX to induce cellular apoptosis and autophagy in breast cancer cells.