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

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

  • Cell Death Dis. 2020 Sep 18;11(9):778. doi: 10.1038/s41419-020-02972-2.
Kai Chen  # 1 2 3,  Qianying Yang  # 4,  Jie Zha  # 2,  Manman Deng 2,  Yong Zhou 2,  Guofeng Fu 4,  Silei Bi 2,  Liying Feng 2,  Zijun Y Xu-Monette 5,  Xiao Lei Chen 4,  Guo Fu 4,  Yun Dai 6,  Ken H Young 7,  Bing Xu 8 9
Affiliations

Affiliations

  • 1 Department of Hematology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China.
  • 2 Department of Hematology, the First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, China.
  • 3 The First People's Hospital of Foshan (The Affiliated Foshan Hospital of Sun Yat-sen University), 528000, Foshan, Guangdong, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, 361102, Xiamen, Fujian, China.
  • 5 Hematopathology Division and Department of Pathology, Duke University School of Medicine, Duke University Medical Center and Cancer Institute, Durham, NC, 27710, USA.
  • 6 Laboratory of Cancer Precision Medicine, Cancer Center, the First Hospital of Jilin University, 130021, Changchun, Jilin, China. daiyun@jlu.edu.cn.
  • 7 Hematopathology Division and Department of Pathology, Duke University School of Medicine, Duke University Medical Center and Cancer Institute, Durham, NC, 27710, USA. kenhyoung@gmail.com.
  • 8 Department of Hematology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, China. xubingzhangjian@126.com.
  • 9 Department of Hematology, the First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, China. xubingzhangjian@126.com.
  • # Contributed equally.
PMID: 32948748 DOI: 10.1038/s41419-020-02972-2
Abstract

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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