Document Detail


Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor.
MedLine Citation:
PMID:  16453001     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NF-kappaB is constitutively activated in adult T-cell leukemia (ATL) and is considered responsible for cell growth and prevention of cell death. In this study, we demonstrate that NF-kappaB is constitutively activated in various HTLV-1-infected T-cell lines and ATL-derived cell lines irrespectively of Tax expression as evidenced by the phosphorylation of IkappaBalpha and p65 subunit of NF-kappaB, activation of NF-kappaB DNA binding, and upregulation of various target genes including bcl-xL, bcl-2, XIAP, c-IAP1, survivin, cyclinD1, ICAM-1 and VCAM-1. The effects of a novel IkappaB kinase (IKK) inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP), were examined on cell growth of these cell lines and fresh ATL leukemic cells. We found that ACHP could inhibit the phosphorylation of IkappaBalpha and p65, as well as NF-kappaB DNA-binding, associated with downregulation of the NF-kappaB target genes and induce cell growth arrest and apoptosis in these cells. When Tax-active and Tax-inactive cell lines were compared, ACHP could preferentially inhibit cell growth of Tax-active cells. Moreover, ACHP exhibited strong apoptosis-inducing activity in fresh ATL cells. These findings indicate that ACHP and its derivatives are effective in inducing ATL cell death and thus feasible candidates for the treatment of ATL.
Authors:
T Sanda; K Asamitsu; H Ogura; S Iida; A Utsunomiya; R Ueda; T Okamoto
Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia     Volume:  20     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-23     Completed Date:  2006-09-08     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  590-8     Citation Subset:  IM    
Affiliation:
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Binding Sites
Cell Cycle / drug effects
Cell Death / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA / metabolism
Drug Screening Assays, Antitumor
Enzyme Activation / drug effects,  genetics,  physiology
Enzyme Inhibitors / pharmacology*
Gene Expression Regulation, Enzymologic / drug effects
Human T-lymphotropic virus 1 / metabolism
Humans
I-kappa B Kinase / antagonists & inhibitors*,  genetics,  metabolism
Leukemia-Lymphoma, Adult T-Cell / metabolism*,  virology
Nicotinic Acids / pharmacology*
Nitriles / pharmacology*
Phosphorylation
Protein Subunits / antagonists & inhibitors,  genetics,  metabolism
Structure-Activity Relationship
T-Lymphocytes / drug effects*,  metabolism,  virology
Transcription Factor RelA / antagonists & inhibitors,  genetics,  metabolism
Chemical
Reg. No./Substance:
0/2-amino-6-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-4-piperidin-4-yl nicotinonitrile; 0/Enzyme Inhibitors; 0/Nicotinic Acids; 0/Nitriles; 0/Protein Subunits; 0/Transcription Factor RelA; 9007-49-2/DNA; EC 2.7.11.10/I-kappa B Kinase

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


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