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Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia.

Publication ,  Journal Article
Chen, K; Yang, Q; Zha, J; Deng, M; Zhou, Y; Fu, G; Bi, S; Feng, L; Xu-Monette, ZY; Chen, XL; Fu, G; Dai, Y; Young, KH; Xu, B
Published in: Cell Death Dis
September 18, 2020

Acute myeloid leukemia (AML) is a heterogeneous myeloid neoplasm with poor clinical outcome, despite the great progress in treatment in recent years. The selective Bcl-2 inhibitor venetoclax (ABT-199) in combination therapy has been approved for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy, but resistance can be acquired through the upregulation of alternative antiapoptotic proteins. Here, we reported that a newly emerged histone deacetylase inhibitor, chidamide (CS055), at low-cytotoxicity dose enhanced the anti-AML activity of ABT-199, while sparing normal hematopoietic progenitor cells. Moreover, we also found that chidamide showed a superior resensitization effect than romidepsin in potentiation of ABT-199 lethality. Inhibition of multiple HDACs rather than some single component might be required. The combination therapy was also effective in primary AML blasts and stem/progenitor cells regardless of disease status and genetic aberrance, as well as in a patient-derived xenograft model carrying FLT3-ITD mutation. Mechanistically, CS055 promoted leukemia suppression through DNA double-strand break and altered unbalance of anti- and pro-apoptotic proteins (e.g., Mcl-1 and Bcl-xL downregulation, and Bim upregulation). Taken together, these results show the high therapeutic potential of ABT-199/CS055 combination in AML treatment, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.

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Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

September 18, 2020

Volume

11

Issue

9

Start / End Page

778

Location

England

Related Subject Headings

  • Sulfonamides
  • Leukemia, Myeloid, Acute
  • Humans
  • Cell Proliferation
  • Bridged Bicyclo Compounds, Heterocyclic
  • Biphenyl Compounds
  • Benzamides
  • Apoptosis Regulatory Proteins
  • Antineoplastic Agents
  • Aminopyridines
 

Citation

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Chen, K., Yang, Q., Zha, J., Deng, M., Zhou, Y., Fu, G., … Xu, B. (2020). Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis, 11(9), 778. https://doi.org/10.1038/s41419-020-02972-2
Chen, Kai, Qianying Yang, Jie Zha, Manman Deng, Yong Zhou, Guofeng Fu, Silei Bi, et al. “Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia.Cell Death Dis 11, no. 9 (September 18, 2020): 778. https://doi.org/10.1038/s41419-020-02972-2.
Chen K, Yang Q, Zha J, Deng M, Zhou Y, Fu G, et al. Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis. 2020 Sep 18;11(9):778.
Chen, Kai, et al. “Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia.Cell Death Dis, vol. 11, no. 9, Sept. 2020, p. 778. Pubmed, doi:10.1038/s41419-020-02972-2.
Chen K, Yang Q, Zha J, Deng M, Zhou Y, Fu G, Bi S, Feng L, Xu-Monette ZY, Chen XL, Dai Y, Young KH, Xu B. Preclinical evaluation of a regimen combining chidamide and ABT-199 in acute myeloid leukemia. Cell Death Dis. 2020 Sep 18;11(9):778.

Published In

Cell Death Dis

DOI

EISSN

2041-4889

Publication Date

September 18, 2020

Volume

11

Issue

9

Start / End Page

778

Location

England

Related Subject Headings

  • Sulfonamides
  • Leukemia, Myeloid, Acute
  • Humans
  • Cell Proliferation
  • Bridged Bicyclo Compounds, Heterocyclic
  • Biphenyl Compounds
  • Benzamides
  • Apoptosis Regulatory Proteins
  • Antineoplastic Agents
  • Aminopyridines