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 - Tập 102 Số 12 - Trang 4584-4589 - 2005
Albena T. Dinkova‐Kostova1, Karen T. Liby1, Katherine K. Stephenson1, W. David Holtzclaw1, Xiangqun Gao1, Nanjoo Suh1, Charlotte R. Williams1, Renee Risingsong1, Tadashi Honda1, Gordon W. Gribble1, Michael B. Sporn1, Paul Talalay1
1The Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21205; and Department of Pharmacology and Toxicology, Dartmouth Medical School, and Department of Chemistry, Dartmouth College, Hanover, NH 03755

Tóm tắt

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 NAD(P)H–quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC 50 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 ( r 2 = 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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 102 Số 12

4584-4589

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