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

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.

• Authors: Weiguang Wang, Howard L McLeod, James Cassidy
• Journal: International journal of cancer (Int J Cancer) Vol. 104 Issue 4 Pg. 504-11 (Apr 20 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12584750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• I-kappa B Proteins
• NF-kappa B
• NFKBIA protein, human
• NF-KappaB Inhibitor alpha
• DNA
• Disulfiram
• Fluorouracil

Topics

• Active Transport, Cell Nucleus (drug effects)
• Apoptosis (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• DNA (metabolism)
• Disulfiram (pharmacology)
• Drug Synergism
• Fluorouracil (pharmacology)
• Humans
• I-kappa B Proteins (metabolism)
• NF-KappaB Inhibitor alpha
• NF-kappa B (antagonists & inhibitors)
• Tumor Cells, Cultured