In this study, we investigated the anti-
tumor activity of
KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a novel synthetic
histone deacetylase (
HDAC) inhibitor.
KBH-A42 inhibited a variety of HDAC
isoforms in
enzyme assays and suppressed growth of various
cancer cell lines. Among the cell lines examined,
colon cancer cells, including SW620, SW480 and HCT-15, were the cell types most sensitive to
KBH-A42.
KBH-A42 inhibition of
cancer cell growth was comparable to or stronger than that of
suberoylanilide hydroxamic acid (SAHA), a well-known
HDAC inhibitor approved by the FDA to treat
cutaneous T cell lymphomas. In SW620 cells,
KBH-A42 increased the acetylation of
histones, mediated cell cycle arrest (G1 arrest at low doses and G2 arrest at high doses), and induced apoptosis. The cell cycle arrest and apoptosis induced by
KBH-A42 might be mediated through up-regulation of p21(Waf1) and activation of
caspases, respectively. In addition,
KBH-A42 inhibited SW620
tumor growth in a human
tumor xenograft model. Taken together, our results indicate that
KBH-A42 exerts an anti-
tumor activity in vitro and in vivo and is a promising therapeutic candidate to treat human
cancers.