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A Novel Acetylenic Tricyclic bis-(Cyano Enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin

¹ Dartmouth Medical School and ² Dartmouth College, Hanover, New Hampshire; ³ Johns Hopkins University, Baltimore, Maryland; and ⁴ Biomedical Research Centre, University of Dundee, Dundee, United Kingdom

Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, 7650 Remsen, Hanover, NH 03755. Phone: 603-650-6558; Fax: 603-650-1129; E-mail: Michael.Sporn{at}dartmouth.edu.

Key Words: chemoprevention • aflatoxin • Nrf2 • triterpenoid • tricyclic bis-enone • TBE-31

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. [Cancer Res 2008;68(16):6727–33]