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

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 16 Pg. 6727-33 (Aug 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18701497 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• DNA Adducts
• Imidazoles
• Phenanthrenes
• Reactive Oxygen Species
• TBE 31
• aflatoxin B1-DNA adduct
• Nitric Oxide
• Oleanolic Acid
• Aflatoxin B1
• Nitric Oxide Synthase Type II
• Heme Oxygenase-1
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• NQO1 protein, rat

Topics

• 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, pathology, prevention & control)
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• Molecular Structure
• NAD(P)H Dehydrogenase (Quinone) (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Phenanthrenes (chemistry, pharmacology)
• Rats
• Rats, Inbred F344
• Reactive Oxygen Species (metabolism)