Document Detail


Inhibition of NF-κB activation sensitizes U937 cells to 3'-azido-3'-deoxythymidine induced apoptosis.
MedLine Citation:
PMID:  21368854     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we investigated molecular mechanisms underlying low susceptibility to apoptosis induced by the nucleoside analog azidothymidine (AZT) and the role of nuclear factor-κB (NF-κB) activation in these phenomena. A preliminary screening in different cell lines indicated U937 monocytic cell line as suitable to this purpose. Treatment of U937 cells even with suprapharmacological concentrations of AZT induced only moderate levels of apoptosis. Surprisingly, SuperArray analysis showed that AZT induced the transcriptional activity of both pro- and anti-apoptotic genes. Interestingly, moreover, several genes upregulated by AZT were NF-κB related. In fact, AZT, after an initial inhibition of NF-κB activation with respect to control, induced a transient, but consistent, increase in NF-κB-binding activity. Inhibition of NF-κB activation in U937 cells, stably transfected with a dominant-negative IκBα or by pharmacological treatment, sensitized them to apoptosis induced by AZT and impaired the upregulation of anti-apoptotic genes in response to AZT treatment, with respect to control cells. These results indicate that NF-κB activation by AZT has a role in protecting target cells from apoptotic cell death, improving our understanding of the toxicology and the therapeutic usage of this drug.
Authors:
C Matteucci; A Minutolo; E Balestrieri; F Marino-Merlo; P Bramanti; E Garaci; B Macchi; A Mastino
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-07
Journal Detail:
Title:  Cell death & disease     Volume:  1     ISSN:  2041-4889     ISO Abbreviation:  Cell Death Dis     Publication Date:  2010  
Date Detail:
Created Date:  2011-03-03     Completed Date:  2011-06-14     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101524092     Medline TA:  Cell Death Dis     Country:  England    
Other Details:
Languages:  eng     Pagination:  e81     Citation Subset:  IM    
Affiliation:
Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', Italy.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites / pharmacology*
Apoptosis*
Gene Expression Regulation, Neoplastic
Humans
NF-kappa B / antagonists & inhibitors,  metabolism*
Oligonucleotide Array Sequence Analysis
U937 Cells
Zidovudine / pharmacology*
Chemical
Reg. No./Substance:
0/Antimetabolites; 0/NF-kappa B; 30516-87-1/Zidovudine
Comments/Corrections

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