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Research Articles: Therapeutics, Targets, and Development

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

¹ Johns Hopkins University, Baltimore, Maryland; ² ERATO Environmental Response Project and ³ Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan; ⁴ National Cancer Institute, Bethesda, Maryland; ⁵ Dartmouth Medical School; ⁶ Dartmouth College, Hanover, New Hampshire; and ⁷ University of Wisconsin, Madison, Wisconsin

Requests for reprints: Thomas W. Kensler, Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Room E7541, 615 North Wolfe Street, Baltimore, MD 21205. Phone: 410-955-4712; Fax: 410-955-0116. E-mail: tkensler{at}jhsph.edu

Abstract

Synthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 µmol/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs. [Mol Cancer Ther 2007;6(1):154–62]

Grant support: NIH grants CA94076 (T.W. Kensler) and CA78814 (M.B. Sporn), National Foundation for Cancer Research (M.B. Sporn), Reata Pharmaceuticals (M.B. Sporn), and ERATO-JST (M. Yamamoto). M.S. Yates was supported by T32 GM08763.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/24/06; revised 10/20/06; accepted 11/27/06.

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