Document Detail


A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways.
MedLine Citation:
PMID:  19644355     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and suberoylanilide hydroxamic acid is used for the treatment of cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI, CG0006, and assessed its antiproliferative effects on the NCI-60 cancer cell panel and cell lines from liver and stomach cancers that are common in Korea. Micromolar levels of CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung, melanoma, ovarian, prostatic, renal, and stomach cancer cell lines. We further analyzed cell death mechanisms activated by CG0006 in HCT116 (colon cancer) and K562 (leukemia) cells. First, to test the activity of CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression. CG0006 increased acetylation of histone 3, histone 4, and tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover, CG0006 increased the mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with CG0006. Western blot analysis showed that CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition, CG0006 activated caspase-9, caspase-3, and caspase-8. These results indicate that CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI CG0006 may be a potent anticancer drug for solid tumors and leukemia.
Authors:
Jung Jin Hwang; Yong Sook Kim; Mi Joung Kim; Sejin Jang; Je-Hwan Lee; Jene Choi; Seonggu Ro; Young-Lan Hyun; Jung Shin Lee; Choung-Soo Kim
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  20     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-09-03     Completed Date:  2009-12-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  815-21     Citation Subset:  IM    
Affiliation:
Institute for Innovative Cancer Research, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
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MeSH Terms
Descriptor/Qualifier:
Acetylation / drug effects
Caspases / metabolism
Cell Cycle / drug effects
Cell Death / drug effects*
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Enzyme Inhibitors / chemistry,  pharmacology*
Gene Expression / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Histone Deacetylase Inhibitors / metabolism*
Histones / metabolism
Humans
Hydroxamic Acids / chemical synthesis,  chemistry,  pharmacology*
Piperidines / chemical synthesis,  pharmacology*
Tubulin / metabolism
bcl-X Protein / genetics,  metabolism
Chemical
Reg. No./Substance:
0/CG 0006; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Hydroxamic Acids; 0/PXD101; 0/Piperidines; 0/Tubulin; 0/bcl-X Protein; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 149647-78-9/vorinostat; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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