Enhanced sensitivity to chemotherapy in esophageal cancer through inhibition of NF-kappaB.
BACKGROUND
Apoptosis induced by chemotherapeutic drugs is blocked by activation of nuclear factor-kappaB (NF-kappaB) in some cancer cell lines. Therefore, inhibition of NF-kappaB by adenoviral delivery of an IkappaBalpha super-repressor (Ad.IkappaBalpha-SR) should make esophageal cancer cells more sensitive to 5- fluorouracil (5-FU) and taxotere chemotherapy.


METHODS
SEG1 and BIC1 human esophageal cancer cells were studied. Chemotherapy-induced NF-kappaB 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.


RESULTS
5-FU and taxotere significantly induced NF-kappaB activation as measured by luciferase reporter assay (P < 0.005) and EMSA. In both cell lines, Ad.IkappaBalpha-SR enhanced apoptosis by caspase 3/7 assay as compared to chemotherapy alone. In SEG1 cells, pre-treatment with Ad.IkappaBalpha-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.IkappaBalpha followed by 5-FU (0.1 mm) or taxotere (0.01 ug/ml) (P < 0.005). Growth inhibition in both cell lines was also significantly increased by pre-treatment with Ad.IkappaBalpha followed by 5-FU (0.01 mm) or taxotere (0.001 ug/ml) (P < 0.0005).


CONCLUSIONS
Treatment with 5-FU or taxotere induced NF-kappaB activation in human esophageal cancer cells. Inhibition of NF-kappaB by Ad.IkappaBalpha-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-kappaB inhibition to improve outcome in patients with esophageal cancer.
Li
Jing
J
Department of Surgery, University of Florida College of Medicine, Gainesville, 32610, USA.
Minnich
Douglas J
DJ
Camp
Ernest R
ER
Brank
Adam
A
Mackay
Sally L D
SL
Hochwald
Steven N
SN
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005472:Fluorouracil / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology
D000970:Antineoplastic Agents; D016328:NF-kappa B; D043823:Taxoids; D000077143:Docetaxel; D008156:Luciferases; D005472:Fluorouracil