A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin

Karen Liby, Mark M. Yore, Bill D. Roebuck, Karen J. Baumgartner, Tadashi Honda, Chitra Sundararajan, Hidenori Yoshizawa, Gordon W. Gribble, Charlotte R. Williams, Renee Risingsong, Darlene B. Royce, Albena T. Dinkova-Kostova, Katherine K. Stephenson, Patricia A. Egner, Melinda S. Yates, John D. Groopman, Thomas W. Kensler, Michael B. Sporn

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    46 Citations (Scopus)

    Abstract

    A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, inducible nitric oxide synthase, activate phase 2 cytoprotective enzymes in vitro and in vivo, block cell proliferation, and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced preneoplastic hepatic lesions in rats by >90%. Because of the two cyano enones in rings A and C, TBE-31 may directly interact with DTT and protein targets such as Keap1 that contain reactive cysteine residues. The above findings suggest that TBE-31 should also be tested for chemoprevention and chemotherapy in relevant models of cancer and against other chronic, degenerative diseases in which inflammation and oxidative stress contribute to disease pathogenesis.

    Original languageEnglish
    Pages (from-to)6727-6733
    Number of pages7
    JournalCancer Research
    Volume68
    Issue number16
    DOIs
    Publication statusPublished - 15 Aug 2008

    Keywords

    • NITRIC-OXIDE PRODUCTION
    • CANCER CHEMOPREVENTIVE AGENTS
    • HIGHLY-ACTIVE INHIBITORS
    • CDDO-IMIDAZOLIDE
    • RING-A
    • COLORECTAL CANCERS
    • MOUSE MACROPHAGES
    • SULFHYDRYL-GROUPS
    • HUMAN BREAST
    • TRITERPENOIDS

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