This Is a Title in Title Case: A Combination of Low-Dose Decitabine and Chidamide Resulted in Synergistic Effects on the Proliferation and Apoptosis of Human Myeloid Leukemia Cell Lines

Introduction: Myeloid leukemia is a malignant disease caused by both genetic and epigenetic changes. Aberrant DNA methylation and histone modifications are prevalent in cancers including leukemia and the process of epigenetic modifications is reversible, which makes them potential treatment targets using specific inhibitors. In this study, we sought to determine the antileukemic effects of low-dose decitabine (one of the most widely used DNA methyltransferase inhibitor) combined with chidamide (a novel orally active histone deacetylase inhibitor) on myeloid leukemia cells by detecting cell proliferation, cell cycle distribution and cell apoptosis to provide a promising regimen for clinical application.

Methods: We conducted CCK-8 assay to determine the effect of low-dose decitabine combinated with chidamide on cell viability, cell cycle distribution analysis by use of flow cytometry accompanied with RT-qPCR and western blotting analysis to reveal its inhibitory mechanism of cell growth, and cell apoptotic analysis also by use of flow cytometry accompanied with RT-qPCR, western blotting analysis, intracellular ROS production and mitochondrial transmembrane potential assay to determine the apoptotic mechanism of combination of low-dose decitabine and chidamide in K562 and THP-1 cells.

Result: Low-dose decitabine and chidamide alone played an inhibitory role in the proliferation of K562 and THP-1 cells in a dose- and time-dependent manner, and the combination of the two enhanced this effect, accompanied by induction of p21 expression and cell cycle arrest at G0/G1 phase. Chidamide instead of decitabine had pronounced effects on the histone H3 acetylation levels of leukemia cells. Meanwhile, combination of the two significantly induced cell apoptosis via mitochondrial transmembrane potential loss, resulting in upregulation of the cell apoptosis-related gene Bax and the protein cleaved PARP-1 and downregulation of antiapoptosis gene Bcl-2, and proteins, including pro-caspase 9, pro-caspase 3 and PARP-1.

Conclusion: Our results provided evidence for the antileukemia effects of low-dose DNA methyltransferase inhibitor decitabine combinated with histone deacetylase inhibitor chidamide in preclinical myeloid leukemia models and suggested that combination of the two showed therapeutic potential for myeloid leukemia treatment.