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.