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 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.
Liby
Karen
K
Dartmouth Medical School, Hanover, NH 03755, USA.
Yore
Mark M
MM
Roebuck
Bill D
BD
Baumgartner
Karen J
KJ
Honda
Tadashi
T
Sundararajan
Chitra
C
Yoshizawa
Hidenori
H
Gribble
Gordon W
GW
Williams
Charlotte R
CR
Risingsong
Renee
R
Royce
Darlene B
DB
Dinkova-Kostova
Albena T
AT
Stephenson
Katherine K
KK
Egner
Patricia A
PA
Yates
Melinda S
MS
Groopman
John D
JD
Kensler
Thomas W
TW
Sporn
Michael B
MB
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
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