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Chemoprevention - Experimental/Molecular: Drug Design and Optimization| December 01 2006

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

Melinda S. Yates;

Melinda S. Yates

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Masafumi Tauchi;

Masafumi Tauchi

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Fumiki Katsuoka;

Fumiki Katsuoka

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Kathleen C. Flanders;

Kathleen C. Flanders

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Karen T. Liby;

Karen T. Liby

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Tadashi Honda;

Tadashi Honda

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Gordon W. Gribble;

Gordon W. Gribble

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Delinda A. Johnson;

Delinda A. Johnson

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Jeffrey A. Johnson;

Jeffrey A. Johnson

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Neal C. Burton;

Neal C. Burton

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Tomás R. Guilarte;

Tomás R. Guilarte

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Masayuki Yamamoto;

Masayuki Yamamoto

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Michael B. Sporn;

Michael B. Sporn

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Thomas W. Kensler

Thomas W. Kensler

Johns Hopkins University, Baltimore, MD; University of Tsukuba, Tsukuba, Japan; National Cancer Institute, Bethesda, MD; Dartmouth Medical School, Hanover, NH; Dartmouth College, Hanover, NH; University of Wisconsin, Madison, WI

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Author & Article Information

Online ISSN: 1538-7755

Print ISSN: 1055-9965

American Association for Cancer Research

2006

Cancer Epidemiol Biomarkers Prev (2006) 15 (12_Supplement): B88.

Abstract

B88

A class of synthetic triterpenoids have been developed which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving upon 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-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, p.o. A structure activity evaluation of 15 additional triterpenoids a) confirmed the importance of Michael acceptor groups on both the A and C rings, b) demonstrated 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. This work was supported by NIH grants CA94076 (T.W. Kensler), CA78814 (M.B. Sporn), the 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.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]

American Association for Cancer Research

2006