补骨脂查尔酮类似物D36通过靶向自噬和凋亡通路诱导急性髓系白血病细胞死亡

Abstract

Purpose Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with high mortality, and it is urgent to find new and optimized treatment strategies for AML. In this study, bavachinin, isolated from Psoralea corylifolia L. exhibiting extensive anti-tumor activity in many solid tumors and a series of its synthesized analogs, were screened for their anti-cancer activity on AML cell lines. Methods The cell viability of AML cells was measured using CCK-8 assays. Cell apoptosis and cell cycle were detected by flow cytometry. The expression of apoptosis-related protein and autophagy-related protein/gene was detected by western blot, immunofluorescence or RT-PCR. Subcutaneous mice tumor model was used to evaluate the anti-cancer activity of D36 in vivo . Results D36 robustly induced AML cells death in a dose-dependent manner with the IC 50 value of 1.0 μM for HL-60 cells and 0.81 μM for MV4-11 cells at 24 h. D36 activated autophagy by inducing the accumulation of LC3B and promoting the autophagy flux. In addition, D36 triggered the extrinsic apoptosis by upregulating the protein level of FAS, cleaved-caspase 8, cleaved-caspase 3 and cleaved-PARP. D36 also blocked the cell cycle at S phase or G 2 /M phase in AML cells. In addition, we find that activation of caspase cascade induced apoptosis and meanwhile activated autophagy, autophagy activation in turns contributes to apoptosis. Furthermore, D36 suppressed the tumor growth in HL-60 AML-bearing mice without obvious side effects. Conclusion This study suggests that D36 is a promising small-molecule for the treatment of acute myeloid leukemia.