Cholangiocarcinoma (CCA) is a
tumor with poor prognosis that is resistant to all currently available treatments. Whether
curcumin, a nutraceutical derived from turmeric (Curcuma longa), has potential therapeutic activity against human CCA was investigated using three CCA cell lines (KKU100, KKU-M156 and KKU-M213). Examination of mitochondrial
dehydrogenase activity,
phosphatidylserine externalization,
esterase staining,
caspase activation and
poly-adenosine diphosphate ribose polymerase cleavage demonstrated that
curcumin inhibited proliferation of and induced apoptosis in these biliary
cancer cells. Colony-formation assay confirmed the growth-inhibitory effect of
curcumin on CCA cells. When examined for the mechanism,
curcumin was found to activate multiple cell signaling pathways in these cells. First, all CCA cells exhibited constitutively active nuclear factor (NF)-κB, and treatment with
curcumin abolished this activation as indicated by
DNA binding, nuclear translocation and p65 phosphorylation. Second,
curcumin suppressed activation of signal transducer and activator of transcription-3 as indicated by decreased phosphorylation at both
tyrosine(705) and
serine(727) and inhibition of janus kinase-1 phosphorylation. Third,
curcumin induced expression of
peroxisome proliferator-activated receptor gamma. Fourth,
curcumin upregulated
death receptors, DR4 and DR5. Fifth,
curcumin suppressed the Akt activation pathway. Sixth,
curcumin inhibited expression of cell survival
proteins such as B-cell lymphoma-2,
B-cell leukemia protein xL,
X-linked inhibitor of apoptosis protein, c-
FLIP, cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2 and
survivin and
proteins linked to cell proliferation, such as
cyclin D1 and c-Myc. Seventh, the growth inhibitory effect of
curcumin was enhanced in the IκB
kinase-deficient cells, the
enzyme required for
nuclear factor-kappaB activation. Overall, our results indicate that
curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus, its activity against CCA should be further investigated.