| Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. | |
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MedLine Citation:
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PMID: 16453001 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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T Sanda; K Asamitsu; H Ogura; S Iida; A Utsunomiya; R Ueda; T Okamoto |
Publication Detail:
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Type: Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Leukemia Volume: 20 ISSN: 0887-6924 ISO Abbreviation: Leukemia Publication Date: 2006 Apr |
Date Detail:
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Created Date: 2006-03-23 Completed Date: 2006-09-08 Revised Date: 2013-03-04 |
Medline Journal Info:
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Nlm Unique ID: 8704895 Medline TA: Leukemia Country: England |
Other Details:
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Languages: eng Pagination: 590-8 Citation Subset: IM |
Affiliation:
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Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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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:
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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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