Gemcitabine is currently the best treatment available for
pancreatic cancer, but the disease develops resistance to the
drug over time. Agents that can either enhance the effects of
gemcitabine or overcome chemoresistance to the
drug are needed for the treatment of
pancreatic cancer.
Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the
transcription factor nuclear factor-kappaB (
NF-kappaB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether
curcumin can sensitize
pancreatic cancer to
gemcitabine in vitro and in vivo. In vitro,
curcumin inhibited the proliferation of various
pancreatic cancer cell lines, potentiated the apoptosis induced by
gemcitabine, and inhibited constitutive
NF-kappaB activation in the cells. In vivo,
tumors from nude mice injected with
pancreatic cancer cells and treated with a combination of
curcumin and
gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus
gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control),
NF-kappaB activation, and expression of
NF-kappaB-regulated gene products (
cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular
inhibitor of apoptosis protein-1,
cyclooxygenase-2,
matrix metalloproteinase, and
vascular endothelial growth factor) compared with
tumors from control mice treated with
olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that
curcumin potentiates the antitumor effects of
gemcitabine in
pancreatic cancer by suppressing proliferation, angiogenesis,
NF-kappaB, and
NF-kappaB-regulated gene products.