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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Carcinoma, Renal Cell / drug therapy*
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Carcinoma, Renal Cell / metabolism
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Female
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylase Inhibitors / therapeutic use*
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Humans
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Hydroxamic Acids / pharmacology
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Hydroxamic Acids / therapeutic use
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Kidney Neoplasms / drug therapy*
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Lactams / chemical synthesis
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Lactams / pharmacology
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Lactams / therapeutic use
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Poly(ADP-ribose) Polymerases / metabolism
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Promoter Regions, Genetic / drug effects
Substances
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Antineoplastic Agents
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Cyclin-Dependent Kinase Inhibitor p21
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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KBH-A145
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Lactams
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Poly(ADP-ribose) Polymerases