Chidamide shows synergistic cytotoxicity with cytarabine via inducing G0/G1 arrest and apoptosis in myelodysplastic syndromes.

Chidamide is a newly designed and synthesized histone deacetylase (HDAC) inhibitor that selectively inhibits HDAC 1, 2, 3, and 10. Our previous study demonstrated that chidamide induces G0/G1 arrest and apoptosis in myelodysplastic syndromes (MDS). Low-dose chemotherapy is effective in treating higher risk MDS patients, and here, we sought to determine whether the combination of chidamide with cytarabine at lowdoses would increase the cytotoxicity to MDS cells. In this study, the combination of chidamide (50 nM) with cytarabine (50 nM) showed synergistic inhibition on cell growth.The mean combination index values were 0.068, 0.158, and 0.226 in SKM-1, MUTZ-1, and KG-1 MDS cell lines, respectively. The combination increased the acetylation levels of histone H3 and decreased HDAC activity in MDS cells.A low concentration (25 and 50 nM) of chidamide combined with low-dose cytarabine (50 nM) inhibited cell proliferation and arrested the cell cycle in the G0/G1 phasevia down-regulating CDK2 and up-regulating p21. Furthermore, the combined treatment induced cell apoptosis via down-regulating Bcl-2 and up-regulating cleaved caspase-3 protein. These results demonstrate the potential utility of combining chidamide and cytarabine in the treatment of MDS.