Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines.

2.50
Hdl Handle:
http://hdl.handle.net/2436/29483
Title:
Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines.
Authors:
Wang, Weiguang; McLeod, Howard; Cassidy, James
Abstract:
5-Fluorouracil (5-FU) is the major chemotherapeutic component for colorectal cancer (CRC) and other types of solid tumours. Resistance of cancer cells to 5-FU is considered the major obstacle for successful chemotherapy. NF-kappaB is a transcription factor. Cancer cells with high NF-kappaB nuclear activity demonstrate robust chemo- and radio-resistance. We demonstrated that nuclear NF-kappaB activity in CRC cell lines, DLD-1 and RKO(WT), was significantly induced by 5-FU in a concentration- and time-dependent manner. 5-FU induced IkappaBalpha degradation and promoted both NF-kappaB nuclear translocation and its DNA binding activity. 5-FU treatment did not influence the activities of AP-1, AP-2, Oct-1, SP-1, CRE-B and TFIID. Disulfiram (DS), a clinically used anti-alcoholism drug, strongly inhibited constitutive and 5-FU-induced NF-kappaB activity in a dose-dependent manner. DS inhibited both NF-kappaB nuclear translocation and DNA binding activity but had no effect on 5-FU-induced IkappaBalpha degradation. Used in combination, DS significantly enhanced the apoptotic effect of 5-FU on DLD-1 and RKO(WT) cell lines and synergistically potentiated the cytotoxicity of 5-FU to both cell lines. DS also effectively abolished 5-FU chemoresistance in a 5-FU resistant cell line H630(5-FU) in vitro. As DS has extensive preclinical and clinical experience, translating its anticancer usage from in vitro study to clinical trials is relatively straightforward.
Citation:
International Journal of Cancer, 104 (4): 504-511
Publisher:
Wiley InterScience
Journal:
International Journal of Cancer.
Issue Date:
2003
URI:
http://hdl.handle.net/2436/29483
DOI:
10.1002/ijc.10972
PubMed ID:
12584750
Additional Links:
http://www3.interscience.wiley.com/journal/102526456/abstract?CRETRY=1&SRETRY=0
Type:
Article
Language:
en
ISSN:
0020-7136
Appears in Collections:
Cancer Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorWang, Weiguang-
dc.contributor.authorMcLeod, Howard-
dc.contributor.authorCassidy, James-
dc.date.accessioned2008-06-04T13:04:43Z-
dc.date.available2008-06-04T13:04:43Z-
dc.date.issued2003-
dc.identifier.citationInternational Journal of Cancer, 104 (4): 504-511en
dc.identifier.issn0020-7136-
dc.identifier.pmid12584750-
dc.identifier.doi10.1002/ijc.10972-
dc.identifier.urihttp://hdl.handle.net/2436/29483-
dc.description.abstract5-Fluorouracil (5-FU) is the major chemotherapeutic component for colorectal cancer (CRC) and other types of solid tumours. Resistance of cancer cells to 5-FU is considered the major obstacle for successful chemotherapy. NF-kappaB is a transcription factor. Cancer cells with high NF-kappaB nuclear activity demonstrate robust chemo- and radio-resistance. We demonstrated that nuclear NF-kappaB activity in CRC cell lines, DLD-1 and RKO(WT), was significantly induced by 5-FU in a concentration- and time-dependent manner. 5-FU induced IkappaBalpha degradation and promoted both NF-kappaB nuclear translocation and its DNA binding activity. 5-FU treatment did not influence the activities of AP-1, AP-2, Oct-1, SP-1, CRE-B and TFIID. Disulfiram (DS), a clinically used anti-alcoholism drug, strongly inhibited constitutive and 5-FU-induced NF-kappaB activity in a dose-dependent manner. DS inhibited both NF-kappaB nuclear translocation and DNA binding activity but had no effect on 5-FU-induced IkappaBalpha degradation. Used in combination, DS significantly enhanced the apoptotic effect of 5-FU on DLD-1 and RKO(WT) cell lines and synergistically potentiated the cytotoxicity of 5-FU to both cell lines. DS also effectively abolished 5-FU chemoresistance in a 5-FU resistant cell line H630(5-FU) in vitro. As DS has extensive preclinical and clinical experience, translating its anticancer usage from in vitro study to clinical trials is relatively straightforward.en
dc.language.isoenen
dc.publisherWiley InterScienceen
dc.relation.urlhttp://www3.interscience.wiley.com/journal/102526456/abstract?CRETRY=1&SRETRY=0en
dc.subjectNF-Ben
dc.subjectIBen
dc.subject5-FUen
dc.subjectDisulfiramen
dc.subjectColorectal canceren
dc.subjectCancer, Colorectal-
dc.subject.meshActive Transport, Cell Nucleusen
dc.subject.meshApoptosisen
dc.subject.meshColorectal Neoplasmsen
dc.subject.meshDNAen
dc.subject.meshDisulfiramen
dc.subject.meshDrug Synergismen
dc.subject.meshFluorouracilen
dc.subject.meshHumansen
dc.subject.meshI-kappa B Proteinsen
dc.subject.meshNF-kappa Ben
dc.subject.meshTumor Cells, Cultureden
dc.titleDisulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines.en
dc.typeArticleen
dc.identifier.journalInternational Journal of Cancer.en

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