A Novel [gamma]-Lactam-Based Histone Deacetylase Inhibitor Potently Inhibits the Growth of Human Breast and Renal Cancer Cells

• Published in: Biological & pharmaceutical bulletin 2009-10, Vol.32 (10), p.1723
• Main Authors: Keun Kwon, Hyoung, Hoon Ahn, Seong, Hong Park, Se, Hyun Park, Jae, Woo Park, Jong, Mook Kim, Hwan, Park, Song-Kyu, Lee, Kiho, Lee, Chang-Woo, Choi, Eunhyun, Han, Gyoonhee, Han, Jeung-Whan
• Format: Article
• Language: English
• ISSN: 0918-6158; 1347-5215

We evaluated the novel γ-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 p21WAF1/Cip1 through compromised recruitment of HDAC1, which leads to hyperacetylation of its promoter region and thus arrested both cells in the G2/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 γ-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.