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

Wang, W., McLeod, H. and Cassidy, J. (2003) Disulfiram-mediated inhibition of NF-kappa B activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. International Journal of Cancer, 104(4), pp. 504-511. (doi: 10.1002/ijc.10972)

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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 RKOWT, 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 RKOWT 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cassidy, Professor James
Authors: Wang, W., McLeod, H., and Cassidy, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:International Journal of Cancer
Publisher:John Wiley and Sons
ISSN:0020-7136

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