Inhibition of inducible NF-kappaB activity reduces chemoresistance to 5-fluorouracil in human stomach cancer cell line

Exp Cell Res. 2003 Sep 10;289(1):27-35. doi: 10.1016/s0014-4827(03)00223-4.

Abstract

5-fluorouracil (5-FU) is used for the treatment of stomach and colon cancer, but many tumors are resistant to this chemotherapeutic agent. 5-FU induces apoptosis of several cancer cell lines, while some chemotherapeutic agents are known to activate the transcriptional factor NF-kappaB, which strongly suppresses apoptosis in vitro. In the present study, we investigated the relationship between activation of NF-kappaB and chemoresistance to 5-FU in human stomach cancer cell lines, NUGC3 (5-FU sensitive) and NUGC3/5FU/L (5-FU resistant). Treatment with 5-FU for 9-12 h caused activation of inducible NF-kappaB in NUGC3/5FU/L cells but not in NUGC3 cells. 5-FU also resulted in an increase in the number of TUNEL-positive cells and enhanced caspase-3 activity 3- to 5-fold in NUGC3 cells but not NUGC3/5FU/L cells. Moreover we also demonstrated that the inhibition of inducible NF-kappaB activation by using a NF-kappaB decoy could induce apoptosis and reduce chemoresistance against 5-FU. Our results suggest that 5-FU chemoresistance can be overcome by inhibition of inducible NF-kappaB activation, and that the use of the NF-kappaB decoy combined with 5-FU treatment is a new molecular and gene therapeutic strategy aimed at treatment of human stomach cancers resistant to 5-FU.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Antimetabolites, Antineoplastic / agonists*
  • Antimetabolites, Antineoplastic / toxicity
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Caspase 3
  • Caspases / drug effects
  • Caspases / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Drug Synergism
  • Fluorouracil / agonists*
  • Fluorouracil / toxicity
  • Humans
  • NF-kappa B / analogs & derivatives*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics
  • Tumor Cells, Cultured

Substances

  • Antimetabolites, Antineoplastic
  • NF-kappa B
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Fluorouracil