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 A. Egner, Melinda S. Yates, John D. 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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Liby, K., Yore, M. M., Roebuck, B. D., Baumgartner, K. J., Honda, T., Sundararajan, C., Yoshizawa, H., Gribble, G. W., Williams, C. R., Risingsong, R., Royce, D. B., Dinkova-Kostova, A. T., Stephenson, K. K., Egner, P. A., Yates, M. S., Groopman, J. D., Kensler, T. W., & Sporn, M. B. (2008). A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin. Cancer Research, 68(16), 6727-6733. https://doi.org/10.1158/0008-5472.CAN-08-1123