| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Cell and Tumor Biology |
1 Dartmouth Medical School and 2 Dartmouth College, Hanover, New Hampshire and 3 University of Alabama at Birmingham, Birmingham, Alabama
Requests for reprints: Michael B. Sporn, Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-6557; Fax: 603-650-1129; E-mail: michael.sporn{at}dartmouth.edu.
The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.
This article has been cited by other articles:
|
|
 |
|
  E. H. Heiss, D. Schachner, E. R. Werner, and V. M. Dirsch Active NF-E2-related Factor (Nrf2) Contributes to Keep Endothelial NO Synthase (eNOS) in the Coupled State: ROLE OF REACTIVE OXYGEN SPECIES (ROS), eNOS, AND HEME OXYGENASE (HO-1) LEVELS J. Biol. Chem., November 13, 2009; 284(46): 31579 - 31586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Pitha-Rowe, K. Liby, D. Royce, and M. Sporn Synthetic Triterpenoids Attenuate Cytotoxic Retinal Injury: Cross-talk between Nrf2 and PI3K/AKT Signaling through Inhibition of the Lipid Phosphatase PTEN Invest. Ophthalmol. Vis. Sci., November 1, 2009; 50(11): 5339 - 5347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Reddy, V. Suryanaraya, M. S. Yates, S. R. Kleeberger, P. M. Hassoun, M. Yamamoto, K. T. Liby, M. B. Sporn, T. W. Kensler, and S. P. Reddy The Triterpenoid CDDO-Imidazolide Confers Potent Protection against Hyperoxic Acute Lung Injury in Mice Am. J. Respir. Crit. Care Med., November 1, 2009; 180(9): 867 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. E. Ferguson, T. H. Thatcher, K. C. Olsen, T. M. Garcia-Bates, C. J. Baglole, R. M. Kottmann, E. R. Strong, R. P. Phipps, and P. J. Sime Peroxisome proliferator-activated receptor-{gamma} ligands induce heme oxygenase-1 in lung fibroblasts by a PPAR{gamma}-independent, glutathione-dependent mechanism Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L912 - L919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, V. Rubio, M. W. Lieberman, and Z.-Z. Shi OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms PNAS, September 8, 2009; 106(36): 15356 - 15361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Yates, Q. T. Tran, P. M. Dolan, W. O. Osburn, S. Shin, C. C. McCulloch, J. B. Silkworth, K. Taguchi, M. Yamamoto, C. R. Williams, et al. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice Carcinogenesis, June 1, 2009; 30(6): 1024 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Reisman, R. L. Yeager, M. Yamamoto, and C. D. Klaassen Increased Nrf2 Activation in Livers from Keap1-Knockdown Mice Increases Expression of Cytoprotective Genes that Detoxify Electrophiles more than those that Detoxify Reactive Oxygen Species Toxicol. Sci., March 1, 2009; 108(1): 35 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Sussan, T. Rangasamy, D. J. Blake, D. Malhotra, H. El-Haddad, D. Bedja, M. S. Yates, P. Kombairaju, M. Yamamoto, K. T. Liby, et al. From the Cover: Targeting Nrf2 with the triterpenoid CDDO- imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice PNAS, January 6, 2009; 106(1): 250 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Baglole, P. J. Sime, and R. P. Phipps Cigarette smoke-induced expression of heme oxygenase-1 in human lung fibroblasts is regulated by intracellular glutathione Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L624 - L636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Liby, M. M. Yore, B. D. Roebuck, K. J. Baumgartner, T. Honda, C. Sundararajan, H. Yoshizawa, G. W. Gribble, C. R. Williams, R. Risingsong, et al. A Novel Acetylenic Tricyclic bis-(Cyano Enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin Cancer Res., August 15, 2008; 68(16): 6727 - 6733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Vannini, G. Lorusso, R. Cammarota, M. Barberis, D. M. Noonan, M. B. Sporn, and A. Albini The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent Mol. Cancer Ther., December 1, 2007; 6(12): 3139 - 3146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Traylor, T. Hock, and N. Hill-Kapturczak Specificity protein 1 and Smad-dependent regulation of human heme oxygenase-1 gene by transforming growth factor-beta1 in renal epithelial cells Am J Physiol Renal Physiol, September 1, 2007; 293(3): F885 - F894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liby, T. Honda, C. R. Williams, R. Risingsong, D. B. Royce, N. Suh, A. T. Dinkova-Kostova, K. K. Stephenson, P. Talalay, C. Sundararajan, et al. Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities Mol. Cancer Ther., July 1, 2007; 6(7): 2113 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liby, D. B. Royce, C. R. Williams, R. Risingsong, M. M. Yore, T. Honda, G. W. Gribble, E. Dmitrovsky, T. A. Sporn, and M. B. Sporn The Synthetic Triterpenoids CDDO-Methyl Ester and CDDO-Ethyl Amide Prevent Lung Cancer Induced by Vinyl Carbamate in A/J Mice Cancer Res., March 15, 2007; 67(6): 2414 - 2419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Hock, K. Liby, M. M. Wright, S. McConnell, M. Schorpp-Kistner, T. M. Ryan, and A. Agarwal JunB and JunD Regulate Human Heme Oxygenase-1 Gene Expression in Renal Epithelial Cells J. Biol. Chem., March 2, 2007; 282(9): 6875 - 6886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Yates, M. Tauchi, F. Katsuoka, K. C. Flanders, K. T. Liby, T. Honda, G. W. Gribble, D. A. Johnson, J. A. Johnson, N. C. Burton, et al. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes Mol. Cancer Ther., January 1, 2007; 6(1): 154 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Yore, K. T. Liby, T. Honda, G. W. Gribble, and M. B. Sporn The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-{kappa}B activation through direct inhibition of I{kappa}B kinase {beta} Mol. Cancer Ther., December 1, 2006; 5(12): 3232 - 3239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. auf dem Keller, M. Huber, T. A. Beyer, A. Kumin, C. Siemes, S. Braun, P. Bugnon, V. Mitropoulos, D. A. Johnson, J. A. Johnson, et al. Nrf Transcription Factors in Keratinocytes Are Essential for Skin Tumor Prevention but Not for Wound Healing Mol. Cell. Biol., May 15, 2006; 26(10): 3773 - 3784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Yates, M.-K. Kwak, P. A. Egner, J. D. Groopman, S. Bodreddigari, T. R. Sutter, K. J. Baumgartner, B.D. Roebuck, K. T. Liby, M. M. Yore, et al. Potent Protection against Aflatoxin-Induced Tumorigenesis through Induction of Nrf2-Regulated Pathways by the Triterpenoid 1-[2-Cyano-3-,12-Dioxooleana-1,9(11)-Dien-28-Oyl]Imidazole Cancer Res., February 15, 2006; 66(4): 2488 - 2494. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
