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

TY - JOUR

T1 - A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin

AU - Liby, Karen

AU - Yore, Mark M.

AU - Roebuck, Bill D.

AU - Baumgartner, Karen J.

AU - Honda, Tadashi

AU - Sundararajan, Chitra

AU - Yoshizawa, Hidenori

AU - Gribble, Gordon W.

AU - Williams, Charlotte R.

AU - Risingsong, Renee

AU - Royce, Darlene B.

AU - Dinkova-Kostova, Albena T.

AU - Stephenson, Katherine K.

AU - Egner, Patricia A.

AU - Yates, Melinda S.

AU - Groopman, John D.

AU - Kensler, Thomas W.

AU - Sporn, Michael B.

PY - 2008/8/15

Y1 - 2008/8/15

N2 - 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.

AB - 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.

KW - NITRIC-OXIDE PRODUCTION

KW - CANCER CHEMOPREVENTIVE AGENTS

KW - HIGHLY-ACTIVE INHIBITORS

KW - CDDO-IMIDAZOLIDE

KW - RING-A

KW - COLORECTAL CANCERS

KW - MOUSE MACROPHAGES

KW - SULFHYDRYL-GROUPS

KW - HUMAN BREAST

KW - TRITERPENOIDS

U2 - 10.1158/0008-5472.CAN-08-1123

DO - 10.1158/0008-5472.CAN-08-1123

M3 - Article

C2 - 18701497

SN - 0008-5472

VL - 68

SP - 6727

EP - 6733

JO - Cancer Research

JF - Cancer Research

IS - 16

ER -