Wen Zhang1, Jingwen Liu1, Yiming Li2, Fujiang Guo3. 1. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, People's Republic of China. 2. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, People's Republic of China. ymli@shutcm.edu.cn. 3. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai, 201203, People's Republic of China. gfj@shutcm.edu.cn.
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 IC50 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 G2/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.
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 IC50 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 G2/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.
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Authors: Courtney D DiNardo; Eytan M Stein; Stéphane de Botton; Gail J Roboz; Jessica K Altman; Alice S Mims; Ronan Swords; Robert H Collins; Gabriel N Mannis; Daniel A Pollyea; Will Donnellan; Amir T Fathi; Arnaud Pigneux; Harry P Erba; Gabrielle T Prince; Anthony S Stein; Geoffrey L Uy; James M Foran; Elie Traer; Robert K Stuart; Martha L Arellano; James L Slack; Mikkael A Sekeres; Christophe Willekens; Sung Choe; Hongfang Wang; Vickie Zhang; Katharine E Yen; Stephanie M Kapsalis; Hua Yang; David Dai; Bin Fan; Meredith Goldwasser; Hua Liu; Sam Agresta; Bin Wu; Eyal C Attar; Martin S Tallman; Richard M Stone; Hagop M Kantarjian Journal: N Engl J Med Date: 2018-06-02 Impact factor: 91.245
Authors: Daniel A Pollyea; Martin S Tallman; Stéphane de Botton; Hagop M Kantarjian; Robert Collins; Anthony S Stein; Mark G Frattini; Qiang Xu; Alessandra Tosolini; Wendy L See; Kyle J MacBeth; Samuel V Agresta; Eyal C Attar; Courtney D DiNardo; Eytan M Stein Journal: Leukemia Date: 2019-04-09 Impact factor: 12.883