The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling.
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.
Liby
Karen
K
Dartmouth Medical School and Dartmouth College, Hanover, New Hampshire 03755, USA.
Hock
Thomas
T
Yore
Mark M
MM
Suh
Nanjoo
N
Place
Andrew E
AE
Risingsong
Renee
R
Williams
Charlotte R
CR
Royce
Darlene B
DB
Honda
Tadashi
T
Honda
Yukiko
Y
Gribble
Gordon W
GW
Hill-Kapturczak
Nathalie
N
Agarwal
Anupam
A
Sporn
Michael B
MB
D000818:Animals; D000975:Antioxidants / Q000502:physiology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008565:Membrane Proteins; D051379:Mice; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018384:Oxidative Stress; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020218:Response Elements / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D020298:U937 Cells
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D007093:Imidazoles; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D009828:Oleanolic Acid; D000242:Cyclic AMP; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse