Chidamide and venetoclax synergistically exert cytotoxicity on multiple myeloma by upregulating BIM expression

  • Clin Epigenetics. 2022 Jul 7;14(1):84. doi: 10.1186/s13148-022-01306-7.
Liqin Cao   #  1  2  3 ,  Qingxiao Chen   #  1  2  3 ,  Huiyao Gu  1  2  3 ,  Yi Li  1  2  3 ,  Wen Cao  1  2  3 ,  Yang Liu  1  2  3 ,  Jianwei Qu  1  2  3 ,  Yifan Hou  1  2  3 ,  Jing Chen  1  2  3 ,  Enfan Zhang  1  2  3 ,  Jingsong He  4  5  6 ,  Zhen Cai  7  8  9
Affiliations
  • 1. Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Rd, Hangzhou, 310003, Zhejiang, China.
  • 2. Institute of Hematology, Zhejiang University, Hangzhou, China.
  • 3. Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China.
  • 4. Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Rd, Hangzhou, 310003, Zhejiang, China. [email protected].
  • 5. Institute of Hematology, Zhejiang University, Hangzhou, China. [email protected].
  • 6. Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China. [email protected].
  • 7. Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Rd, Hangzhou, 310003, Zhejiang, China. [email protected].
  • 8. Institute of Hematology, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 35799216 DOI: 10.1186/s13148-022-01306-7
Abstract

Background: Multiple myeloma (MM) is the second most common hematologic malignancy with almost all patients eventually having relapse or refractory MM (RRMM), thus novel drugs or combination therapies are needed for improved prognosis. Chidamide and venetoclax, which target histone deacetylase and BCL2, respectively, are two promising agents for the treatment of RRMM.

Results: Herein, we found that chidamide and venetoclax synergistically exert an anti-myeloma effect in vitro in human myeloma cell lines (HMCLs) with a combination index (CI) < 1. Moreover, the synergistic anti-myeloma effect of these two drugs was demonstrated in primary MM cells and MM xenograft mice. Mechanistically, co-exposure to chidamide and venetoclax led to cell cycle arrest at G0/G1 and a sharp increase in DNA double-strand breaks. In addition, the combination of chidamide and venetoclax resulted in BCL-XL downregulation and Bim upregulation, and the latter protein was proved to play a critical role in sensitizing HMCLs to co-treatment.

Conclusion: In conclusion, these results proved the high therapeutic potential of venetoclax and chidamide combination in curing MM, representing a potent and alternative salvage therapy for the treatment of RRMM.

Keywords
BIM; Cell cycle arrest; Chidamide; DNA damage; HDAC inhibitor; Multiple myeloma; Venetoclax.
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