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.