Enhanced radiosensitization and chemosensitization in NF-kappaB-suppressed human oral cancer cells via the inhibition of gamma-irradiation- and 5-FU-induced production of IL-6 and IL-8

Int J Cancer. 2004 Mar 1;108(6):912-21. doi: 10.1002/ijc.11640.

Abstract

We examined the mechanisms underlying the enhancement of radiosensitivity and chemosensitivity to gamma-irradiation (IR) and 5-Fluorouracil (5-FU) in human oral carcinoma cells (B88) in which NF-kappaB activity was constitutively suppressed. Three super-repressor form of IkappaBalpha cDNA-transfected cell (B88mI) clones and 1 empty vector-transfected cell clone (B88neo) have been established. We found that the tumor-forming ability in nude mice of B88mI clones was significantly lower than that of B88 or B88neo. This suppressed ability in tumorigenicity was attributed to the down-regulation of the expression of interleukin (IL)-1alpha, IL-6, IL-8, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 in B88mI cell clones as compared to that in B88 or B88neo. IR and 5-FU induced a much greater degree of apoptosis, as evidenced by flow cytometry analysis and annexin V staining, in B88mI cell clones than in B88 or B88neo. When tumor-bearing nude mice were treated with IR or 5-FU, the suppression of tumor growth was significantly augmented in B88mI cell clones as compared to that in B88 or B88neo. ELISA analysis indicated that although a remarkable increase in production of IL-6 and IL-8 was observed in B88 and B88neo after in vitro exposure to IR or treatment with 5-FU, radiotherapy and chemotherapy-induced production of these cytokines was significantly suppressed in B88mI cell clones. These findings suggest that production of angiogenic factors and growth factors in response to radiotherapy and chemotherapy is a principal mechanism of inducible radioresistance and chemoresistance in human oral cancers, and establish the inhibition of NF-kappaB as a rational approach to improve conventional radiotherapy and chemotherapy outcomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / pharmacology
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis
  • Blotting, Western
  • Carcinoma / drug therapy
  • Carcinoma / radiotherapy
  • Cell Division
  • Cell Nucleus / metabolism
  • Cell Separation
  • Culture Media, Conditioned / pharmacology
  • Cytosol / metabolism
  • DNA, Complementary / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorouracil / pharmacology*
  • Gamma Rays
  • Genetic Vectors
  • Humans
  • I-kappa B Proteins / metabolism
  • Immunohistochemistry
  • Interleukin-6 / biosynthesis*
  • Interleukin-8 / biosynthesis*
  • Luciferases / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Nude
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / radiotherapy*
  • Mutation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Neovascularization, Pathologic
  • Oligonucleotides / pharmacology
  • Time Factors
  • Transfection
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Annexin A5
  • Antimetabolites, Antineoplastic
  • Culture Media, Conditioned
  • DNA, Complementary
  • I-kappa B Proteins
  • Interleukin-6
  • Interleukin-8
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Oligonucleotides
  • Vascular Endothelial Growth Factor A
  • NF-KappaB Inhibitor alpha
  • Luciferases
  • Matrix Metalloproteinase 9
  • Fluorouracil