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A combination of low-dose decitabine and chidamide resulted in synergistic effects on the proliferation and apoptosis of human myeloid leukemia cell lines.

ABSTRACT: Two of the most common and well-characterized epigenetic changes, DNA methylation and histone modifications, occur in leukemia. Decitabine (5-aza-2'-deoxycytidine, DAC), as a hypomethylating agent (HMA), and chidamide (CS055), as a histone deacetylase inhibitor (HDACi), each demonstrate effects against leukemia. However, whether the combination of low-dose DAC with chidamide constitutes an effective epigenetic regimen for the treatment of myeloid leukemia is currently unknown. In this study, the combination of DAC at low doses and chidamide showed enhanced inhibition of myeloid leukemia cell (K562, THP-1) growth. As a novel HDACi, chidamide increased the level of ace-H3K18 expression. Combined use of low-dose DAC and chidamide arrested the cell cycle at the G0/G1 phase by upregulating p21 expression, and the combination also suppressed PI3K/AKT/mTOR signaling pathway. Furthermore, chidamide enhanced the apoptotic effect of DAC by downregulating expression of Bcl-2 and pro-caspase-3 and upregulating that of Bax, cleaved PARP-1, and caspase-9. Moreover, the mitochondrial transmembrane potential was significantly decreased in DAC-, chidamide-, or combination-treated leukemia cells. These results suggest that targeting the leukemia epigenome through the combination of low-dose DAC and chidamide is a promising approach.

SUBMITTER: Xu F

PROVIDER: S-EPMC6943475 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A combination of low-dose decitabine and chidamide resulted in synergistic effects on the proliferation and apoptosis of human myeloid leukemia cell lines.

Xu Fangfang F Guo Honggang H Shi Mingyue M Liu Siwei S Wei Min M Sun Kai K Chen Yuqing Y

American journal of translational research 20191215 12

Two of the most common and well-characterized epigenetic changes, DNA methylation and histone modifications, occur in leukemia. Decitabine (5-aza-2'-deoxycytidine, DAC), as a hypomethylating agent (HMA), and chidamide (CS055), as a histone deacetylase inhibitor (HDACi), each demonstrate effects against leukemia. However, whether the combination of low-dose DAC with chidamide constitutes an effective epigenetic regimen for the treatment of myeloid leukemia is currently unknown. In this study, the ...[more]

PMID: 31934307

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Project description:BackgroundMore effective targeted therapy and new combination regimens are needed for Acute myeloid leukemia (AML), owing to the unsatisfactory long-term prognosis of the disease. Here, we investigated the synergistic effect and the mechanism of a histone deacetylase inhibitor, Chidamide in combination with Cladribine, a purine nucleoside antimetabolite analog in the disease.MethodsCell counting kit-8 assays and Chou-Talalay's combination index were used to examine the synergistic effect of Chidamide and Cladribine on AML cell lines (U937, THP-1, and MV4-11) and primary AML cells. PI and Annexin-V/PI assays were used to detect the cell cycle effect and apoptosis effect, respectively. Global transcriptome analysis, RT-qPCR, c-MYC Knockdown, western blotting, co-immunoprecipitation, and chromatin immunoprecipitation assays were employed to explore the molecule mechanisms.ResultsThe combination of Chidamide with Cladribine showed a significant increase in cell proliferation arrest, the G0/G1 phase arrest, and apoptosis compared to the single drug control in AML cell lines along with upregulated p21Waf1/Cip1 expression and downregulated CDK2/Cyclin E2 complex, and elevated cleaved caspase-9, caspase-3, and PARP. The combination significantly suppresses the c-MYC expression in AML cells, and c-MYC knockdown significantly increased the sensitivity of U937 cells to the combination compared to single drug control. Moreover, we observed HDAC2 interacts with c-Myc in AML cells, and we further identified that c-Myc binds to the promoter region of RCC1 that also could be suppressed by the combination through c-Myc-dependent. Consistently, a positive correlation of RCC1 with c-MYC was observed in the AML patient cohort. Also, RCC1 and HDAC2 high expression are associated with poor survival in AML patients. Finally, we also observed the combination significantly suppresses cell growth and induces the apoptosis of primary cells in AML patients with AML1-ETO fusion, c-KIT mutation, MLL-AF6 fusion, FLT3-ITD mutation, and in a CMML-BP patient with complex karyotype.ConclusionsOur results demonstrated the synergistic effect of Chidamide with Cladribine on cell growth arrest, cell cycle arrest, and apoptosis in AML and primary cells with genetic defects by targeting HDAC2/c-Myc/RCC1 signaling in AML. Our data provide experimental evidence for the undergoing clinical trial (Clinical Trial ID: NCT05330364) of Chidamide plus Cladribine as a new potential regimen in AML.

Dataset Information

A combination of low-dose decitabine and chidamide resulted in synergistic effects on the proliferation and apoptosis of human myeloid leukemia cell lines.

Publications

A combination of low-dose decitabine and chidamide resulted in synergistic effects on the proliferation and apoptosis of human myeloid leukemia cell lines.

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