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

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.

Chidamide: Targeting epigenetic regulation in the treatment of hematological malignancy

“…Chidamide was also demonstrated to inhibit the proliferation of MM cells by decreasing the expression of nuclear factor (NF)‐κB 43 . Chidamide demonstrated synergistic anti‐myeloma effect with venetoclax in Bcl‐XL downregulation and BIM upregulation in human myeloma cell lines, primary MM cells and MM xenograft mice 41 …”

“…Currently, chidamide has been reported to inhibit proliferation, invasion and promote apoptosis of MM cells. [39][40][41] Chidamide was reported to induce G0/G1 phase arrest in MM cells. 40 After treatment with chidamide, the expression of cell cycle positive regulators cyclin D and cyclin E is downregulated, which in turn inhibits cell cycle from G1 phase to S phase.…”

“…43 Chidamide demonstrated synergistic anti-myeloma effect with venetoclax in Bcl-XL downregulation and BIM upregulation in human myeloma cell lines, primary MM cells and MM xenograft mice. 41 Figure 1 presents a schematic overview of the mechanisms of chidamide in the regulation of the cell cycle, proliferation, ROS and apoptosis.…”

“…Currently, chidamide has been reported to inhibit proliferation, invasion and promote apoptosis of MM cells 39–41 . Chidamide was reported to induce G0/G1 phase arrest in MM cells 40 .…”

Metformin and chidamide synergistically suppress multiple myeloma progression and enhance lenalidomide/bortezomib sensitivity

“…[17][18][19] The combination treatment of chidamide and venetoclax is indicated to suppress the cell cycle process and induce DNA damage in MM cells by positively regulating Bcl-2 interacting mediator of cell death (BIM) expression. 20 In the current work, we intended to analyze the combination of metformin and chidamide on the growth, glucose metabolism and…”