| Inhibition of NF-kappaB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin. | |
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MedLine Citation:
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PMID: 11314019 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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A Arlt; J Vorndamm; M Breitenbroich; U R Fölsch; H Kalthoff; W E Schmidt; H Schäfer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Oncogene Volume: 20 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2001 Feb |
Date Detail:
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Created Date: 2001-04-23 Completed Date: 2001-05-10 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 859-68 Citation Subset: IM |
Affiliation:
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Laboratory of Molecular Gastroenterology, 1st Department of Medicine, University of Kiel, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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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:
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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:
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Oncogene 2002 Apr 11;21(16):2611 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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