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

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 Egner, Melinda S. Yates, John Davis Groopman, Thomas W Kensler, Michael B. Sporn

Research output: Contribution to journalArticle

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 Keapl 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.

Original languageEnglish (US)
Pages (from-to)6727-6733
Number of pages7
JournalCancer Research
Volume68
Issue number16
DOIs
StatePublished - Aug 15 2008

Fingerprint

Aflatoxins
Carcinogenesis
Liver
DNA Adducts
Chemoprevention
Nitric Oxide Synthase Type II
Cysteine
Oral Administration
Leukemia
Proteins
Oxidative Stress
Chronic Disease
Cell Proliferation
Apoptosis
Inflammation
Drug Therapy
TBE 31
Enzymes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. / 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; Yates, Melinda S.; Groopman, John Davis; Kensler, Thomas W; Sporn, Michael B.

In: Cancer Research, Vol. 68, No. 16, 15.08.2008, p. 6727-6733.

Research output: Contribution to journalArticle

Liby, K, Yore, MM, Roebuck, BD, Baumgartner, KJ, Honda, T, Sundararajan, C, Yoshizawa, H, Gribble, GW, Williams, CR, Risingsong, R, Royce, DB, Dinkova-Kostova, AT, Stephenson, KK, Egner, P, Yates, MS, Groopman, JD, Kensler, TW & Sporn, MB 2008, 'A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin', Cancer Research, vol. 68, no. 16, pp. 6727-6733. https://doi.org/10.1158/0008-5472.CAN-08-1123
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 ; Yates, Melinda S. ; Groopman, John Davis ; Kensler, Thomas W ; Sporn, Michael B. / A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. In: Cancer Research. 2008 ; Vol. 68, No. 16. pp. 6727-6733.
@article{b832e4db93c04b17b89d0cea6428a0d4,
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 Keapl 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.",
author = "Karen Liby and Yore, {Mark M.} and Roebuck, {Bill D.} and Baumgartner, {Karen J.} and Tadashi Honda and Chitra Sundararajan and Hidenori Yoshizawa and Gribble, {Gordon W.} and Williams, {Charlotte R.} and Renee Risingsong and Royce, {Darlene B.} and Dinkova-Kostova, {Albena T.} and Stephenson, {Katherine K.} and Patricia Egner and Yates, {Melinda S.} and Groopman, {John Davis} and Kensler, {Thomas W} and Sporn, {Michael B.}",
year = "2008",
month = "8",
day = "15",
doi = "10.1158/0008-5472.CAN-08-1123",
language = "English (US)",
volume = "68",
pages = "6727--6733",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

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

AU - Yates, Melinda S.

AU - Groopman, John Davis

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 Keapl 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 Keapl 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.

UR - http://www.scopus.com/inward/record.url?scp=53049090607&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53049090607&partnerID=8YFLogxK

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

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

M3 - Article

C2 - 18701497

AN - SCOPUS:53049090607

VL - 68

SP - 6727

EP - 6733

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 16

ER -