Document Detail


Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.
MedLine Citation:
PMID:  11314019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The transcription factor NF-kappaB has anti-apoptotic properties and may confer chemoresistance to cancer cells. Here, we describe human pancreatic carcinoma cell lines that differ in the responsiveness to the topoisomerase-2 inhibitors VP16 (20 microM) and doxorubicin (0.3 microM): Highly sensitive T3M4 [corrected] and PT45-P1 cells, and Capan-1 and A818-4 cells that were almost resistant to both anti cancer drugs. VP16, but not doxorubicin, transiently induced NF-kappaB activity in all cell lines, whereas basal NF-kappaB binding was nearly undetectable in T3M4 [corrected] and PT45-P1 cells, but rather high in Capan-1 and A818-4 cells, as demonstrated by gel-shift and luciferase assays. Treatment with various NF-kappaB inhibitors (Gliotoxin, MG132 and Sulfasalazine), or transfection with the IkappaBalpha super-repressor, strongly enhanced the apoptotic effects of VP16 or doxorubicin on resistant Capan-1 and 818-4 cells. Our results indicate that under certain conditions the resistance of pancreatic carcinoma cells to chemotherapy is due to their constitutive NF-kappaB activity rather than the transient induction of NF-kappaB by some anti-cancer drugs. Blockade of basal NF-kappaB activity by well established drugs efficiently reduces chemoresistance of pancreatic cancer cells and offers the potential for improved therapeutic strategies.
Authors:
A Arlt; J Vorndamm; M Breitenbroich; U R Fölsch; H Kalthoff; W E Schmidt; H Schäfer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  20     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2001 Feb 
Date Detail:
Created Date:  2001-04-23     Completed Date:  2001-05-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  859-68     Citation Subset:  IM    
Affiliation:
Laboratory of Molecular Gastroenterology, 1st Department of Medicine, University of Kiel, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Carcinoma / drug therapy*
DNA-Binding Proteins / biosynthesis
Doxorubicin / pharmacology*
Drug Resistance
Etoposide / pharmacology*
Gliotoxin / pharmacology
Humans
I-kappa B Proteins*
Leupeptins / pharmacology
NF-kappa B / antagonists & inhibitors*
Pancreatic Neoplasms / drug therapy*
Sulfasalazine / pharmacology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/DNA-Binding Proteins; 0/I-kappa B Proteins; 0/Leupeptins; 0/NF-kappa B; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 139874-52-5/NF-kappaB inhibitor alpha; 23214-92-8/Doxorubicin; 33419-42-0/Etoposide; 599-79-1/Sulfasalazine; 67-99-2/Gliotoxin
Comments/Corrections
Erratum In:
Oncogene 2002 Apr 11;21(16):2611

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


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