Inducible nuclear factor-κB activation contributes to chemotherapy resistance in gastric cancer - 24/08/11
, Jing Li, MA , Douglas J Minnich, MD , Adam Brank, PhD , Lyle L Moldawer, PhD , Sally LD MacKay, PhD , Steven N Hochwald, MD ⁎, , †, ‡ : FACS Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA Abstract |
Background |
Activation of nuclear factor-κB (NF-κB) inhibits chemotherapy-induced apoptosis in some cancer cell lines. Inhibition of NF-κB by adenoviral delivery of an IκB⍺ superrepressor (Ad.IκB⍺-SR) should potentiate 5-fluorouracil (5-FU) and irinotecan chemotherapy in gastric cancer cells.
Study design |
NCI-N87 and AGS human gastric cancer cells were studied. Chemotherapy-induced NF-κB activation was assessed using a luciferase reporter assay. Inhibition of NF-κB was assessed by luciferase reporter assay and by electrophoretic mobility shift assay. Cells were pretreated for 1 hour with Ad.IκB⍺ (25 MOI) and incubated with 5-FU or the active metabolite of irinotecan (SN-38). Cell growth was assessed by cell proliferation assay and induction of apoptosis was determined by flow cytometry and caspase 3/7 assay.
Results |
5-FU and SN-38 significantly induced NF-κB activation as measured by luciferase reporter assay (p < 0.001). Ad.IκB⍺-SR treatment inhibited NF-κB binding as demonstrated by electrophoretic mobility shift assay and by luciferase reporter assay. In AGS cells, pretreatment with Ad.IκB⍺-SR followed by 5-FU (0.005 mmol/L) or SN-38 (10 ng/mL) led to increased growth inhibition of 13% and 59%, respectively (p < 0.001). Similarly, growth inhibition in NCI cells was significantly increased by pretreatment with Ad.IκB⍺ followed by 5-FU (0.001 mmol/L) or SN-38 (0.5 ng/mL) (p < 0.001). In both cell lines, Ad.IκB⍺-SR enhanced apoptosis by both flow cytometry and caspase 3/7 assay as compared with chemotherapy alone.
Conclusions |
NF-κB is activated in human gastric cancer in response to chemotherapy and may result in inducible chemoresistance. Inhibition of NF-κB by Ad.IκB⍺-SR enhances the antitumor effects of chemotherapy and has potential as a novel antineoplastic strategy.
Le texte complet de cet article est disponible en PDF.Abbreviations : Adgfp, Ad.IκB⍺-SR, CPT-11, EMSA, 5-FU, NF-κB, SN-38
Plan
 | Supported by the Florida Biomedical Research Program. |
Vol 199 - N° 2
P. 249-258 - août 2004 Retour au numéro
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