A novel delta-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells.
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.
Kang
Moo Rim
MR
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Yangcheong, Ochang, Cheongwon, Chungbuk, Republic of Korea.
Kang
Jong Soon
JS
Han
Sang-Bae
SB
Kim
Jang Hyun
JH
Kim
Dong-Myung
DM
Lee
Kiho
K
Lee
Chang Woo
CW
Lee
Ki Hoon
KH
Lee
Chul Ho
CH
Han
Gyoonhee
G
Kang
Jong Seong
JS
Kim
Hwan Mook
HM
Park
Song-Kyu
SK
D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007769:Lactams / Q000494:pharmacology*; D034741:RNA, Small Interfering
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007769:Lactams; D034741:RNA, Small Interfering