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A bavachinin analog, D36, induces cell death by targeting both autophagy and apoptosis pathway in acute myeloid leukemia cells

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.

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Availability of data and materials

The data that support the findings of this study may be available from the corresponding author upon request.

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Acknowledgements

This work was supported by the National Natural Science Fund (Grant Number: 81872763).

Funding

National Natural Science Foundation of China, 81872763, Fujiang Guo

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WZ: Conceptualization, data curation, formal analysis, Validation, methodology, writing-original draft. JL: Methodology, investigation. YL: Conceptualization, resources, supervision, funding acquisition. FG: Conceptualization, resources, supervision, funding acquisition, project administration, writing-review & editing.

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Correspondence to Yiming Li or Fujiang Guo.

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Zhang, W., Liu, J., Li, Y. et al. A bavachinin analog, D36, induces cell death by targeting both autophagy and apoptosis pathway in acute myeloid leukemia cells. Cancer Chemother Pharmacol 90, 251–265 (2022). https://doi.org/10.1007/s00280-022-04462-y

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Keywords

  • Bavachinin analogs
  • Acute myeloid leukemia
  • Autophagy
  • Apoptosis
  • Cell cycle