title: Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer.
abstract: BACKGROUND
  5-fluorouracil (5-FU), the most common antimetabolite used for the treatment of colorectal cancer, exerts its cytotoxic effects through the induction of apoptosis. Folinic acid potentiates the effect of 5-FU. Drug activity is currently limited as a result of inducible chemoresistance. Limited research suggests that the transcription factor nuclear factor kappa-B (NF-kappaB), which has antiapoptotic properties, may play a major role in inducible chemoresistance.
  
  
  METHODS
  SW48 colon cancer cells were used for all experiments. Cell growth was determined by cell proliferation assay. Apoptosis was assessed by measuring caspase 3 activity. Activation of NF-kappaB was ascertained by electrophoretic mobility shift assay, luciferase reporter assay, and Western blot analysis.
  
  
  RESULTS
  Treatment with 5-FU (0.001-10 mm), not only inhibited growth and induced apoptosis but significantly activated NF-kappaB in SW48 cells. Folinic acid alone (0.01-100 mg/L) did not inhibit growth but improved the cytotoxic effect of 5-FU in a dose-dependent manner. Likewise, folinic acid alone did not activate NF-kappaB or induce apoptosis but enhanced 5-FU-mediated NF-kappaB activation and cell apoptosis. Transfection with adenovirus IkappaBalpha super-repressor strongly inhibited constitutive activation of NF-kappaB and significantly enhanced 5-FU and 5-FU/Folinic acid-mediated growth inhibition (P < 0.05).
  
  
  CONCLUSIONS
  Treatment with 5-FU activates NF-kappaB. Folinic acid enhances 5-FU-mediated activation of NF-kappaB. Inhibition of NF-kappaB enhances the cytotoxic effect of 5-FU with or without Folinic acid in colon cancer cells.
authors.affiliation: Department of Surgery, Division of Surgical Oncology, University of Florida College of Medicine, 1600 SW Archer Road, Room 6184, Gainesville, FL 32610, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Voboril
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hochwald
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Adam
authors.initials: A
authors.lastname: Brank
authors.forename: Jana
authors.initials: J
authors.lastname: Weberova
authors.forename: Frank
authors.initials: F
authors.lastname: Wessels
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: E Ramsay
authors.initials: ER
authors.lastname: Camp
authors.forename: Sally L D
authors.initials: SL
authors.lastname: MacKay
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D005822:Genetic Vectors; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000494:pharmacology; D002955:Leucovorin / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D014162:Transfection
chemical_list: D000964:Antimetabolites, Antineoplastic; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D002955:Leucovorin; D005472:Fluorouracil