Nuclear factor‐κB and IκB kinase are constitutively active in human pancreatic cells, and their down‐regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis

Abstract

BACKGROUND: Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option—gemcitabine—yielding response rates of < 10%. Because nuclear factor‐κB (NF‐κB) has been determined to play a role in cell survival/proliferation in human pancreatic carcinoma, this transcription factor is a potential therapeutic target. METHODS: The authors investigated the ability of curcumin (diferuloylmethane), an agent that is pharmacologically safe in humans, to modulate NF‐κB activity. RESULTS: NF‐κB and IκB kinase (IKK) were constitutively active in all human pancreatic carcinoma cell lines examined, and curcumin consistently suppressed NF‐κB binding (as assessed using an electrophoretic mobility gel‐shift assay) and IKK activity. Curcumin decreased the expression of NF‐κB–regulated gene products, including cyclooxygenase‐2 (as assessed using immunoblot analysis), prostaglandin E 2, and interleukin‐8 (as assessed using an enzyme‐linked immunoassay), all of which have been implicated in the growth and invasiveness of pancreatic carcinoma. These changes were associated with concentration‐ and time‐dependent antiproliferative activity (as assessed using a 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide [MTT] assay) and proapoptotic effects (as assessed via annexin V/propidium iodide staining [fluorescence‐activated cell sorting, as well as with the induction of polyadenosine‐5′‐diphosphate‐ribose polymerase cleavage). CONCLUSIONS: Curcumin down‐regulated NF‐κB and growth control molecules induced by NF‐κB in human pancreatic cells. These effects were accompanied by marked growth inhibition and apoptosis. Through these findings, the authors provided a biologic rationale for the treatment of patients with pancreatic carcinoma using this nontoxic phytochemical. Cancer 2004. © 2004 American Cancer Society.