Inhibition of NF-kappa B augments sensitivity to 5-fluorouracil/folinic acid in colon cancer

• Published in: The Journal of surgical research 2004-08, Vol.120 (2), p.178-188
• Main Authors: VOBORIL, Rene, HOCHWALD, Steven N, JING LI, BRANK, Adam, WEBEROVA, Jana, WESSELS, Frank, MOLDAWER, Lyle L, CAMP, E. Ramsay, MACKAY, Sally L. D
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Antimetabolites, Antineoplastic - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Cell Line, Tumor; Colonic Neoplasms - pathology; Colonic Neoplasms - physiopathology; Drug Synergism; Fluorouracil - pharmacology; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Genetic Vectors; Humans; I-kappa B Proteins - genetics; I-kappa B Proteins - pharmacology; Leucovorin - pharmacology; Medical sciences; NF-kappa B - antagonists & inhibitors; NF-kappa B - drug effects; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transfection; Tumors
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2003.11.023

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. 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. 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). 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.