A novel gamma-lactam-based histone deacetylase inhibitor potently inhibits the growth of human breast and renal cancer cells.

Abstract

We evaluated the novel gamma-lactam-based analogue, KBH-A145, for its anticancer activities. KBH-A145 markedly inhibited histone deacetylase (HDAC) activity in vitro and in vivo to an extent comparable to suberoyl-anilide hydroxamic acid (SAHA). The proliferation of various types of cancers was significantly suppressed by KBH-A145, among which MDA-MB-231 and MCF, human breast cancer cells and ACHN human renal cancer cells, were most sensitive. This was accompanied by induction of p21(WAF1/Cip1) through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G(2)/M phase. Interestingly, this compound induced apoptosis of MDA-MB-231 cells, but not ACHN cells, through cleavage of poly(ADP-ribose) polymerase (PARP). Taken together, these results show that this novel gamma-lactam-based HDAC inhibitor potently inhibits the growth of human breast and renal cancer cells. Thus KBH-A145 is a potential therapeutic agent for the treatment of these types of cancer.

• Authors: Hyoung Keun Kwon, Seong Hoon Ahn, Se Hong Park, Jae Hyun Park, Jong Woo Park, Hwan Mook Kim, Song-Kyu Park, Kiho Lee, Chang-Woo Lee, Eunhyun Choi, Gyoonhee Han, Jeung-Whan Han
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 32 Issue 10 Pg. 1723-7 (Oct 2009) ISSN: 1347-5215 [Electronic] Japan
• PMID: 19801834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• KBH-A145
• Lactams
• Poly(ADP-ribose) Polymerases

Topics

• Acetylation
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Carcinoma, Renal Cell (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Female
• Histone Deacetylase Inhibitors (chemical synthesis, pharmacology, therapeutic use)
• Humans
• Hydroxamic Acids (pharmacology, therapeutic use)
• Kidney Neoplasms (drug therapy)
• Lactams (chemical synthesis, pharmacology, therapeutic use)
• Poly(ADP-ribose) Polymerases (metabolism)
• Promoter Regions, Genetic (drug effects)