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Disulfiram‐mediated inhibition of NF‐κB activity enhances cytotoxicity of 5‐fluorouracil in human colorectal cancer cell lines
Author(s) -
Wang Weiguang,
McLeod Howard L.,
Cassidy James
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10972
Subject(s) - cell culture , cytotoxicity , cancer research , apoptosis , pharmacology , in vitro , colorectal cancer , chemistry , cancer , biology , medicine , biochemistry , genetics
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‐κB is a transcription factor. Cancer cells with high NF‐κB nuclear activity demonstrate robust chemo‐ and radio‐resistance. We demonstrated that nuclear NF‐κB 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 IκBα degradation and promoted both NF‐κB 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‐κB activity in a dose‐dependent manner. DS inhibited both NF‐κB nuclear translocation and DNA binding activity but had no effect on 5‐FU‐induced IκBα 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. © 2003 Wiley‐Liss, Inc.