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

Authors

  • Lan Li M.S.,

    1. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Bharat B. Aggarwal Ph.D.,

    1. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Shishir Shishodia Ph.D.,

    1. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • James Abbruzzese M.D.,

    1. Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Razelle Kurzrock M.D.

    Corresponding author
    1. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    2. Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    3. Phase 1 Program, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
    • Phase 1 Program, Division of Cancer Medicine, P.O. Box 422, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
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    • Fax: (713) 745-2374


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 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-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.

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