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

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 synth...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2008-08, Vol.68 (16), p.6727-6733
Main Authors: Liby, Karen, Yore, Mark M, Roebuck, Bill D, Baumgartner, Karen J, Honda, Tadashi, Sundararajan, Chitra, Yoshizawa, Hidenori, Gribble, Gordon W, Williams, Charlotte R, Risingsong, Renee, Royce, Darlene B, Dinkova-Kostova, Albena T, Stephenson, Katherine K, Egner, Patricia A, Yates, Melinda S, Groopman, John D, Kensler, Thomas W, Sporn, Michael B
Format: Article
Language:English
Subjects:
Administration, Oral
Aflatoxin B1 - metabolism
Animals
Apoptosis - drug effects
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Cell Transformation, Neoplastic - drug effects
Cells, Cultured
DNA Adducts - metabolism
Heme Oxygenase-1 - metabolism
Humans
Imidazoles - pharmacology
Leukemia - drug therapy
Liver Neoplasms - chemically induced
Liver Neoplasms - pathology
Liver Neoplasms - prevention & control
Macrophages - cytology
Macrophages - drug effects
Macrophages - metabolism
Male
Mice
Molecular Structure
NAD(P)H Dehydrogenase (Quinone) - metabolism
Nitric Oxide - metabolism
Nitric Oxide Synthase Type II - antagonists & inhibitors
Nitric Oxide Synthase Type II - metabolism
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - pharmacology
Phenanthrenes - chemistry
Phenanthrenes - pharmacology
Rats
Rats, Inbred F344
Reactive Oxygen Species - metabolism
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-08-1123