The
transcription factor,
nuclear factor kappaB (
NF-kappaB), plays a central role as a key mediator of cell survival and proliferation, and its activation may confer increased
tumor chemoresistance.
Curcumin, an orally available naturally occurring compound, has been shown to inhibit
NF-kappaB and has a potential role in
cancer chemoprevention. We investigated the effects of
curcumin on
NF-kappaB activity, on cell viability, and as a chemosensitizing agent with
5-fluorouracil (5-FU) or
cisplatin (CDDP) in esophageal
adenocarcinoma (EAC).
Oligonucleotide microarray analysis of 46 cases, consisting of
Barrett metaplasia, low-grade dysplasia, high-grade dysplasia and EAC, showed increased expression of
NF-kappaB and
IkappaB kinase subunits and decreased effector
caspase expression in EAC compared with
Barrett metaplasia. Stromal expression of both IkappaB and phospho-IkappaB was detected in several EAC samples by tissue microarray analysis.
Curcumin alone inhibited
NF-kappaB activity and induced apoptosis in both Flo-1 and OE33 EAC cell lines as determined by Western blot analysis,
NF-kappaB reporter assays, and
Caspase-Glo 3/7 assays. It also increased 5-FU- and CDDP-induced apoptosis in both cell lines. These data suggest that activation of
NF-kappaB and inhibition of apoptosis may play a role in the progression from
Barrett metaplasia to EAC. In addition,
curcumin, a well-known inhibitor of
NF-kappaB activity, was shown to increase apoptosis and enhance both 5-FU- and CDDP-mediated chemosensitivity, suggesting that it may have potential application in the
therapy of patients with EAC.