title: 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.affiliation: Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Liby
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yore
authors.forename: Bill D
authors.initials: BD
authors.lastname: Roebuck
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Baumgartner
authors.forename: Tadashi
authors.initials: T
authors.lastname: Honda
authors.forename: Chitra
authors.initials: C
authors.lastname: Sundararajan
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Gribble
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Stephenson
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Egner
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Yates
authors.forename: John D
authors.initials: JD
authors.lastname: Groopman
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
mesh_terms: D000284:Administration, Oral; D016604:Aflatoxin B1 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D018736:DNA Adducts; D007093:Imidazoles; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C531972:TBE 31; C072611:aflatoxin B1-DNA adduct; D009569:Nitric Oxide; D009828:Oleanolic Acid; D016604:Aflatoxin B1; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C507703:NQO1 protein, rat