Synergistic effect of chidamide and venetoclax on apoptosis in acute myeloid leukemia cells and its mechanism

Abstract

Background: Acute myeloid leukemia (AML) is a hematological malignancy with a low remission rate and high recurrence rate. Overexpression of the antiapoptotic protein Bcl-2 is associated with a lower overall survival rate in AML patients. Venetoclax (ABT199) is a selective inhibitor of Bcl-2 that has a significant effect in AML, but single-drug resistance often occurs due to the high expression of Mcl-1 protein. Studies have confirmed that chidamide can downregulate the expression levels of Bcl-2 and Mcl-1 and induce apoptosis. Methods: This study aimed to use AML cell lines and primary cells to study the effects of venetoclax and chidamide combination therapy on AML cell apoptosis, the cell cycle, and changes in related signaling pathways in vitro; establish an AML mouse model to observe the efficacy and survival time of combination therapy in vivo; and analyze the drug effects with multi-omics sequencing technology. The changes in gene and protein expression before and after treatment were examined to clarify the molecular mechanism driving the synergistic effect of the two drugs. Results: (I) Both venetoclax and chidamide promoted apoptosis in AML cell lines and primary cells in a time-and concentration-dependent manner. The effect was further enhanced when the two drugs were combined, and a synergistic effect was observed (combination index <1). (II) At both the mRNA and protein levels, the expression of Mcl-1 was upregulated by venetoclax and downregulated by chidamide, and the expression of Mcl-1 decreased further after combination treatment. (III) Transcriptome sequencing showed that differentially expressed genes in the combination group compared with the venetoclax monotherapy group were mainly enriched in the PI3K-AKT pathway and JAK2/STAT3 pathway. Moreover, qRT-PCR and Western blot confirmed these results. (IV) The combination therapy group exhibited significantly inhibited disease progression and a prolonged survival time among AML mice. Conclusions: Chidamide combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting activation of the PI3K/AKT pathway and JAK2/STAT3 pathway.

Current treatment strategies targeting histone deacetylase inhibitors in acute lymphocytic leukemia: a systematic review

“…Furthermore, similar strategies involving SAHA and decitabine have been tested in clinical trials and have shown promising effects in patients with relapsed ALL ( 18 , 19 , 65 ). Low doses of decitabine and SAHA caused cell death in leukemic cells and reduced p21 levels without significant changes in normal peripheral blood lymphocytes ( 66 ). Additionally, pretreatment with SAHA and decitabine can enhance the cytotoxicity of chemotherapy in relapsed childhood B-ALL, suggesting that epigenetic mechanisms play a role in the acquisition of chemoresistance during ALL recurrence ( 67 ).…”

Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax

“…In some types of leukemia and lymphoma, cancer cells evade the natural mechanism of apoptosis by overexpressing Bcl-2, leading to the oversurvival of cancer cells [ 23 ]. During Venetoclax treatment, acquired drug resistance is a common phenomenon, and the compensatory high expression of Mcl-1 may be one of the causes of drug resistance in AML cells [ 24 ]. According to previous reports, both class I HDAC inhibitors and Venetoclax could induce apoptosis and perform a synergistic effect [ 24 ].…”

“…During Venetoclax treatment, acquired drug resistance is a common phenomenon, and the compensatory high expression of Mcl-1 may be one of the causes of drug resistance in AML cells [ 24 ]. According to previous reports, both class I HDAC inhibitors and Venetoclax could induce apoptosis and perform a synergistic effect [ 24 ]. As the IC 50 of 25c measured in the above experiments was 340.1 ± 82.5 nM in the MV4-11 cell line, showing the more obvious effect among the four cell lines, we selected the MV4-11 cell line for the combination cell assay and analyzed the data according to the Chou–Talalay method [ 25 ].…”

Complete elimination of hyperleukocytosis risk in AML through early high-quality disease remission

“…Recent studies ( 14 – 16 ) have shown promising results with the combination therapy of venetoclax and other targeted drugs. For example, the combination of venetoclax, azacitidine, and daunorubicin achieved a higher complete remission rate in newly diagnosed acute monocytic leukemia patients.…”