Novel Synthetic Histone Deacetylase Inhibitor, SK-7041, Has Potent Anti-Proliferative Activity in Acute Myeloid Leukemia Cell Lines.

Histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities determine the acetylation status of histones, which regulates gene expression through chromatin remodeling. Aberrant histone acetylation is known to play a key role in leukemogenesis. Thus, histone deacetylase inhibitors (HDACIs) are emerging as a new class of anti-cancer agents for leukemia. In this study, we examined anti-proliferative effects of novel hybrid synthetic HDACI, SK-7041, in various acute myelogenous leukemia (AML) cell lines (KG-1, HL-60, HEL, U937, ML-1). SK-7041 induced the time-dependent hyperacetylation of histones H3 and H4 in AML cell lines. It preferentially inhibited the enzymatic activities of HDAC1 and HDAC2, as compared with the other HDAC isotypes, indicating that class I HDAC is the major target of SK-7041. All the cell lines tested showed similar patterns of growth inhibition by SK-7041. Their IC₅₀ values were approximately 0.5 mM at 72 hours incubation. SK-7041 effectively induced the apoptosis via activation of caspase-3, -7, -9, and PARP, but not caspase-8. SK-7041 enhanced G1 arrest via decreasing Cyclin D1 expression and increasing p21 expression. Changes in gene expression profiles after treating KG-1 cells with various concentrations of SK-7041 were assessed using a cDNA microarray consisting of distinct cDNAs of cancer-related genes. 7 genes, namely RGL1, FYN, CARD9, ABCA7, TNFRSF6B, CASP9, and ENPP2 were induced substantially (Global M >2.0) and 8 genes, namely PTPN7, CD34, INSIG1, IL16, LHX6, TRIB3, BID, and PDCD4 were reduced substantially (Global M < 2.0). In conclusion, this study showed SK-7041 inhibited cancer cell growth and caused characteristic gene expression profile changes in AML cells. The alteration in levels of acetylated histones was closely associated with expression of specific cancer-related genes in AML cells.