Novel Synthetic Histone Deacetylase Inhibitor (SK-7041) Potently Inhibits Proliferation in Acute Myeloid Leukemia Cell Lines.

Abstract

Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities determine the acetylation status of histones, and have the ability to regulate gene expression through chromatin remodeling. Aberrant histone acetylation is known to play a key role in leukemogenesis. To improve the treatment outcome in AML patients, we examined the antiproliferative activity of SK-7041, a novel hybrid synthetic HDACI, in acute myelogenous leukemia (AML) cell lines (KG-1,HL-60 and HEL). This HDACI preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, compared to other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041. SK-7041 effectively induced the time-dependent hyperacetylation of histones, H3 and H4 in AML cell lines. We found that this compound exhibited potent antiproliferative activity against AML cell lines in vitro. The growth inhibitory effect of SK-7041 was related to the induction of apoptosis in AML cell lines. SK-7041(4uM) induced potent cell death, triggering apoptosis in over 60% of cells in 48h by FACS analysis. After 12h of treatment by western analysis, apoptotic cells were increased through activation of caspase-7,-9,-3 and cleaved-PARP (caspase-8 was not affected). Cyclin D1 expression was decreased, and CDK4 expression level was not affected by SK-7041. The level of p21 expression was gradually increased in KG-1 and HL-60 cell lines, whereas treated HEL cell lines showed no change. For further investigation of the genes affected by SK-7041, 20Kb oligonucleotide microarray analysis was performed. The expression of candidate genes, which we selected in chip analysis, was confirmed using real-time PCR. Fifteen genes (RGL1, FYN, CARD9, ABCA7, TNFRSF6B, CASP9, ENPP2, etc.) were consistently up-regulated and twelve genes (PTPN7, CD34, INSIG1, IL16, LHX6, TRIB3, BID, PDCD4, etc.) were down-regulated more than 4-fold by the SK-7041 compound. We suggest that the efficacy of SK-7041 was mainly mediated by the inhibition of proliferation and induction of apoptosis. Taken together, our data suggested that novel HDACI SK-7041 treatment is effective in AML cell lines, and that the further study is warranted.