Nuclear factor-kappaB and IkappaB 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

Cancer. 2004 Nov 15;101(10):2351-62. doi: 10.1002/cncr.20605.

Abstract

Background: Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option-gemcitabine-yielding response rates of < 10%. Because nuclear factor-kappaB (NF-kappaB) 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-kappaB activity.

Results: NF-kappaB and IkappaB kinase (IKK) were constitutively active in all human pancreatic carcinoma cell lines examined, and curcumin consistently suppressed NF-kappaB binding (as assessed using an electrophoretic mobility gel-shift assay) and IKK activity. Curcumin decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (as assessed using immunoblot analysis), prostaglandin E2, 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-kappaB and growth control molecules induced by NF-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Curcumin / pharmacology*
  • Down-Regulation
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • I-kappa B Kinase
  • Immunoblotting
  • Interleukin-8 / metabolism
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • Pancreatic Neoplasms / metabolism*
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Antineoplastic Agents
  • Interleukin-8
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Curcumin