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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:In the present study, the ability of the proteasome inhibitor bortezomib (BZ), an oxidative stress-inducing agent, to sensitize acute myeloid leukemia (AML) cells to decitabine (Dacogen®, DAC; a DNA methyltransferase inhibitor), in terms of cell viability and differentiation, was investigated. Kasumi-1 AML (M2) cells were treated with low-dose DAC (10, 50, 100, 200 or 400 nΜ), with or without BZ (10 nM). Apoptosis and the cell cycle were evaluated after 24 h of treatment through fluorescence-assisted cell sorting (FACS) with Annexin V/propidium iodide and DAPI staining, respectively. The expression levels of CD193, CD11b, CD13, CD14, CD15, CD16 and CD117 surface differentiation markers were evaluated by FACS after 6 days of treatment. The results indicated significant alterations in cell death and cell cycle phases in Kasumi-1 cells following DAC and BZ combination treatment compared to untreated cells and cells with single treatments. Low-dose DAC/BZ combinations significantly enhanced apoptosis and decreased the population of live Kasumi-1 cells, with 100 and 200 nM of DAC and 10 nM BZ appearing to have the most potent synergistic effect according to a combination index. Furthermore, cell cycle profiling revealed that DAC/BZ treatment synergistically led to G0/G1- and G2/M-phase arrest. By contrast, DAC appeared to promote monocytic and granulocytic differentiation of Kasumi-1 cells more effectively alone than in combination with BZ. BZ acted synergistically with low-dose DAC in vitro, leading to enhanced apoptosis and G0/G1- and G2/M-phase arrest in AML cells, hence prohibiting either DNA synthesis or mitosis. Although further in vivo investigation is necessary, these results provide a strong rationale for the implementation of a combination treatment with DAC and bortezomib in AML therapy, followed by DAC alone, which may achieve better clinical responses and possibly partially overcome the frequently encountered DAC resistance of patients with 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.

Similar Datasets

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