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

• Published in: International journal of cancer 2004-03, Vol.108 (6), p.912
• Main Authors: Tamatani, Tetsuya, Azuma, Masayuki, Ashida, Yuki, Motegi, Katsumi, Takashima, Rina, Harada, Koji, Kawaguchi, Shin-ichi, Sato, Mitsunobu
• Format: Article
• Language: English
• Subjects: 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; Neovascularization, Pathologic; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Oligonucleotides - pharmacology; Time Factors; Transfection; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0020-7136

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.