Metformin Inhibits Acute Myeloid Leukemia Cells Growth through the AMPK/mTOR Pathway and Autophagic Regulation

Metformin (MET) can be used to slow the aging process and treat cancers. Although reports indicate the efficacy of MET combined with other treatments on acute myeloid leukemia (AML), the detailed mechanisms of its effect on AML remain unresolved. This study aimed to find a potential effective strategy of AML by analyzing the inhibitory mechanisms of MET on AML. The effect of MET on AML cell growth was examined by treating Kasumi-1, HL-60, and U937 cells with MET ranging between 0.5 and 40 mM for 72 h. MET was found to markedly inhibit the growth of all AML cell lines in a dose-dependent manner. The mechanism of growth inhibition by MET was further investigated by examining the cell-cycle profile using flow cytometry after treating AML cells with 10 mM MET for 36 h. MET treated groups presented the majority of cells in the G0/G1 phase of the cell cycle vs. the control groups. We also showed that the level of green fluorescence increased in Kasumi-1, HL-60, and U937 cells treated with MET for 72 h at various concentrations using the TUNEL apoptosis kit. The role of MET in inhibiting AML cells was explored by inducing autophagy both in AML cell lines and primary AML cells. Following treatment with 10 mM MET for 36 h, MET-treated group clearly had more phagophores than untreated cells. The mechanisms underlying the anti-proliferative effects of MET were investigated by characterizing the effects of MET on the AMPK/mTOR pathway. In addition, flow cytometry showed that knockdown of AMPK abrogated MET-induced AML cell cycle arrest. Moreover, a combined MET and daunorubicin treatment gave an additive effect in vitro and in vivo. The results suggest that MET could inhibit AML growth by targeting multiple signaling pathways, and MET combined treatment may be a promising therapy for AML.

No relevant conflicts of interest to declare.