A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells

Moo Rim Kang, Jong Soon Kang, Sang Bae Han, Jang Hyun Kim, Dong Myung Kim, Kiho Lee, Chang Woo Lee, Ki Hoon Lee, Chul Ho Lee, Gyoonhee Han, Jong Seong Kang, Hwan Mook Kim, Song Kyu Park

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Abstract

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)pr opanamide], 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 p21Waf1 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.

Original languageEnglish
Pages (from-to)486-494
Number of pages9
JournalBiochemical Pharmacology
Volume78
Issue number5
DOIs
Publication statusPublished - 2009 Sep 1

Fingerprint

Lactams
Histone Deacetylase Inhibitors
Cell Cycle Checkpoints
Colonic Neoplasms
Cells
Apoptosis
Tumors
Neoplasms
Growth
G1 Phase Cell Cycle Checkpoints
Cell Line
Cutaneous T-Cell Lymphoma
Acetylation
Histone Deacetylases
T-cells
KBH A42
Enzyme Assays
Cell growth
Caspases
Heterografts

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Kang, Moo Rim ; Kang, Jong Soon ; Han, Sang Bae ; Kim, Jang Hyun ; Kim, Dong Myung ; Lee, Kiho ; Lee, Chang Woo ; Lee, Ki Hoon ; Lee, Chul Ho ; Han, Gyoonhee ; Kang, Jong Seong ; Kim, Hwan Mook ; Park, Song Kyu. / A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells. In: Biochemical Pharmacology. 2009 ; Vol. 78, No. 5. pp. 486-494.
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title = "A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells",
abstract = "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)pr opanamide], 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 p21Waf1 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.",
author = "Kang, {Moo Rim} and Kang, {Jong Soon} and Han, {Sang Bae} and Kim, {Jang Hyun} and Kim, {Dong Myung} and Kiho Lee and Lee, {Chang Woo} and Lee, {Ki Hoon} and Lee, {Chul Ho} and Gyoonhee Han and Kang, {Jong Seong} and Kim, {Hwan Mook} and Park, {Song Kyu}",
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Kang, MR, Kang, JS, Han, SB, Kim, JH, Kim, DM, Lee, K, Lee, CW, Lee, KH, Lee, CH, Han, G, Kang, JS, Kim, HM & Park, SK 2009, 'A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells', Biochemical Pharmacology, vol. 78, no. 5, pp. 486-494. https://doi.org/10.1016/j.bcp.2009.05.010

A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells. / Kang, Moo Rim; Kang, Jong Soon; Han, Sang Bae; Kim, Jang Hyun; Kim, Dong Myung; Lee, Kiho; Lee, Chang Woo; Lee, Ki Hoon; Lee, Chul Ho; Han, Gyoonhee; Kang, Jong Seong; Kim, Hwan Mook; Park, Song Kyu.

In: Biochemical Pharmacology, Vol. 78, No. 5, 01.09.2009, p. 486-494.

Research output: Contribution to journalArticle

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T1 - A novel δ-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells

AU - Kang, Moo Rim

AU - Kang, Jong Soon

AU - Han, Sang Bae

AU - Kim, Jang Hyun

AU - Kim, Dong Myung

AU - Lee, Kiho

AU - Lee, Chang Woo

AU - Lee, Ki Hoon

AU - Lee, Chul Ho

AU - Han, Gyoonhee

AU - Kang, Jong Seong

AU - Kim, Hwan Mook

AU - Park, Song Kyu

PY - 2009/9/1

Y1 - 2009/9/1

N2 - 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)pr opanamide], 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 p21Waf1 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.

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