Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress

Albena T. Dinkova-Kostova, Karen T. Liby, Katherine K. Stephenson, W. David Holtzclaw, Xiangqun Gao, Nanjoo Suh, Charlotte Williams, Renee Risingsong, Tadashi Honda, Gordon W. Gribble, Michael B. Sporn, Paul Talalay

Research output: Contribution to journalArticle

Abstract

A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2-/- and keap1-/- mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles MAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r2 = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.

Original languageEnglish (US)
Pages (from-to)4584-4589
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number12
DOIs
StatePublished - Mar 22 2005

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Keywords

  • Inflammation
  • NAD(P)H-quinone acceptor oxidoreductase
  • Nrf2 Keap1
  • Oxidative stress
  • Phase 2 enzymes

ASJC Scopus subject areas

  • General

Cite this

Dinkova-Kostova, A. T., Liby, K. T., Stephenson, K. K., Holtzclaw, W. D., Gao, X., Suh, N., Williams, C., Risingsong, R., Honda, T., Gribble, G. W., Sporn, M. B., & Talalay, P. (2005). Extremely potent triterpenoid inducers of the phase 2 response: Correlations of protection against oxidant and inflammatory stress. Proceedings of the National Academy of Sciences of the United States of America, 102(12), 4584-4589. https://doi.org/10.1073/pnas.0500815102