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

Weiguang Wang, H. L. McLeod, J. Cassidy

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    161 Citations (Scopus)

    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. (C) 2003 Wiley-Liss, Inc.

    Original languageEnglish
    Pages (from-to)504-511
    Number of pages7
    JournalInternational Journal of Cancer
    Volume104
    Issue number4
    DOIs
    Publication statusPublished - 2003

    Keywords

    • NF-kappa B
    • I kappa B alpha
    • 5-FU
    • disulfiram
    • colorectal cancer
    • INDUCED APOPTOSIS
    • INDUCIBLE CHEMORESISTANCE
    • TRANSCRIPTION FACTORS
    • BONE-MARROW
    • IN-VITRO
    • ACTIVATION
    • ALPHA
    • DIETHYLDITHIOCARBAMATE
    • INDUCTION
    • TOXICITY

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