Enhanced Sensitivity to Chemotherapy in Esophageal Cancer through Inhibition of NF-κB 1

BackgroundApoptosis induced by chemotherapeutic drugs is blocked by activation of nuclear factor-κB (NF-κB) in some cancer cell lines. Therefore, inhibition of NF-κB by adenoviral delivery of an IκBα super-repressor (Ad.IκBα-SR) should make esophageal cancer cells more sensitive to 5- fluorouracil (5-FU) and taxotere chemotherapy.Materials and methodsSEG1 and BIC1 human esophageal cancer cells were studied. Chemotherapy-induced NF-κB activation was assessed by luciferase reporter assay and by electrophoretic mobility shift assay (EMSA). Cell growth inhibition was assessed by cell proliferation assay. Apoptosis was determined by flow cytometry and caspase 3/7 assay.Results5-FU and taxotere significantly induced NF-κB activation as measured by luciferase reporter assay (P < 0.005) and EMSA. In both cell lines, Ad.IκBα-SR enhanced apoptosis by caspase 3/7 assay as compared to chemotherapy alone. In SEG1 cells, pre-treatment with Ad.IκBα-SR followed by 5-FU (0.25 mm) or taxotere (0.01 ug/ml), led to an increased apoptosis of 183% and 55%, respectively (P < 0.005). Similarly, apoptosis in BIC1 cells was significantly increased by pre-treatment with Ad.IκBα followed by 5-FU (0.1 mm) or taxotere (0.01ug/ml) (P < 0.005). Growth inhibition in both cell lines was also significantly increased by pre-treatment with Ad.IκBα followed by 5-FU (0.01 mm) or taxotere (0.001 ug/ml) (P < 0.0005).ConclusionTreatment with 5-FU or taxotere induced NF-κB activation in human esophageal cancer cells. Inhibition of NF-κB by Ad.IκBα-SR increased their sensitivity to 5-FU and taxotere chemotherapy. Therefore, these results may provide the basis for novel clinical approaches using cytoxic therapy with NF-κB inhibition to improve outcome in patients with esophageal cancer.