| Reference | 1. Carcinogenesis. 2015 Jul;36(7):769-81. doi: 10.1093/carcin/bgv061. Epub 2015 May
4. <br />
<br />
Dimethyl fumarate and the oleanane triterpenoids, CDDO-imidazolide and
CDDO-methyl ester, both activate the Nrf2 pathway but have opposite effects in
the A/J model of lung carcinogenesis. <br />
<br />
To C(1), Ringelberg CS(2), Royce DB(1), Williams CR(1), Risingsong R(1), Sporn
MB(1), Liby KT(3). <br />
Author information: <br />
(1)Department of Pharmacology.
(2)Department of Genetics and.
(3)Department of Pharmacology, Department of Medicine, Geisel School of Medicine
at Dartmouth, Hanover, NH 03755, USA [email protected]. <br />
<br />
Lung cancer accounts for the highest number of cancer-related deaths in the USA,
highlighting the need for better prevention and therapy. Activation of the Nrf2
pathway detoxifies harmful insults and reduces oxidative stress, thus preventing
carcinogenesis in various preclinical models. However, constitutive activation of
the Nrf2 pathway has been detected in numerous cancers, which confers a survival
advantage to tumor cells and a poor prognosis. In our study, we compared the
effects of two clinically relevant classes of Nrf2 activators, dimethyl fumarate
(DMF) and the synthetic oleanane triterpenoids, CDDO-imidazolide (CDDO-Im) and
CDDO-methyl ester (CDDO-Me) in RAW 264.7 mouse macrophage-like cells, in VC1 lung
cancer cells and in the A/J model of lung cancer. Although the triterpenoids and
DMF both activated the Nrf2 pathway, CDDO-Im and CDDO-Me were markedly more
potent than DMF. All of these drugs reduced the production of reactive oxygen
species and inhibited nitric oxide production in RAW264.7 cells, but the
triterpenoids were 100 times more potent than DMF in these assays. Microarray
analysis revealed that only 52 of 99 Nrf2-target genes were induced by all three
compounds, and each drug regulated a unique subset of Nrf2 genes. These drugs
also altered the expression of other genes important in lung cancer independent
of Nrf2. Although all three compounds enhanced the phosphorylation of CREB, only
DMF increased the phosphorylation of Akt. CDDO-Me, at either 12.5 or 50mg/kg of
diet, was the most effective drug in our lung cancer mouse model. Specifically,
CDDO-Me significantly reduced the average tumor number, size and burden compared
with the control group (P < 0.05). Additionally, 52% of the tumors in the control
group were high-grade tumors compared with only 14% in the CDDO-Me group. Though
less potent, CDDO-Im had similar activity as CDDO-Me. In contrast, 61-63% of the
tumors in the DMF groups (400-1200mg/kg diet) were high-grade tumors compared
with 52% for the controls (P < 0.05). Additionally, DMF significantly increased
the average number of tumors compared with the controls (P < 0.05). Thus, in
contrast to the triterpenoids, which effectively reduced pathogenesis in A/J
mice, DMF enhanced the severity of lung carcinogenesis in these mice.
Collectively, these results suggest that although CDDO-Im, CDDO-Me and DMF all
activate the Nrf2 pathway, they target distinct genes and signaling pathways,
resulting in opposite effects for the prevention of experimental lung cancer. <br />
<br />
2. J Neuroinflammation. 2008 May 12;5:14. doi: 10.1186/1742-2094-5-14. <br />
<br />
The synthetic triterpenoid CDDO-methyl ester modulates microglial activities,
inhibits TNF production, and provides dopaminergic neuroprotection. <br />
<br />
Tran TA(1), McCoy MK, Sporn MB, Tansey MG. <br />
Author information: <br />
(1)Department of Physiology, The University of Texas Southwestern Medical Center,
Dallas, Texas, USA. [email protected] <br />
<br />
BACKGROUND: Recent animal and human studies implicate chronic activation of
microglia in the progressive loss of CNS neurons. The inflammatory mechanisms
that have neurotoxic effects and contribute to neurodegeneration need to be
elucidated and specifically targeted without interfering with the neuroprotective
effects of glial activities. Synthetic triterpenoid analogs of oleanolic acid,
such as methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me, RTA 402) have
potent anti-proliferative and differentiating effects on tumor cells, and
anti-inflammatory activities on activated macrophages. We hypothesized that
CDDO-Me may be able to suppress neurotoxic microglial activities while enhancing
those that promote neuronal survival. Therefore, the aims of our study were to
identify specific microglial activities modulated by CDDO-Me in vitro, and to
determine the extent to which this modulation affords neuroprotection against
inflammatory stimuli.<br />
METHODS: We tested the synthetic triterpenoid<br />
methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me, RTA 402) in various in
vitro assays using the murine BV2 microglia cell line, mouse primary microglia,
or mouse primary peritoneal macrophages to investigate its effects on
proliferation, inflammatory gene expression, cytokine secretion, and
phagocytosis. The antioxidant and neuroprotective effects of CDDO-Me were also
investigated in primary neuron/glia cultures from rat basal forebrain or ventral
midbrain.<br />
RESULTS: We found that at low nanomolar concentrations, treatment of rat primary
mesencephalon neuron/glia cultures with CDDO-Me resulted in attenuated LPS-, TNF-
or fibrillar amyloid beta 1-42 (A beta 1-42) peptide-induced increases in
reactive microglia and inflammatory gene expression without an overall effect on
cell viability. In functional assays CDDO-Me blocked death in the dopaminergic
neuron-like cell line MN9D induced by conditioned media (CM) of LPS-stimulated
BV2 microglia, but did not block cell death induced by addition of TNF to MN9D
cells, suggesting that dopaminergic neuroprotection by CDDO-Me involved
inhibition of microglial-derived cytokine production and not direct inhibition of
TNF-dependent pro-apoptotic pathways. Multiplexed immunoassays of CM from
LPS-stimulated microglia confirmed that CDDO-Me-treated BV2 cells produced
decreased levels of specific subsets of cytokines, in particular TNF. Lastly,
CDDO-Me enhanced phagocytic activity of BV2 cells in a stimulus-specific manner
but inhibited generation of reactive oxygen species (ROS) in mixed neuron/glia
basal forebrain cultures and dopaminergic cells.<br />
CONCLUSION: The neuroimmune modulatory properties of CDDO-Me indicate that this
potent antioxidant and anti-inflammatory compound may have therapeutic potential
to modify the course of neurodegenerative diseases characterized by chronic
neuroinflammation and amyloid deposition. The extent to which synthetic
triterpenoids afford therapeutic benefit in animal models of Parkinson/’s and
Alzheimer/’s disease deserves further investigation. <br />
<br />
3. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3139-46. Epub 2007 Dec 7. <br />
<br />
The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent
antiangiogenic agent. <br />
Vannini N(1), Lorusso G, Cammarota R, Barberis M, Noonan DM, Sporn MB, Albini A. <br />
Author information: <br />
(1)Multimedica IRCCS, Milan, Italy. <br />
<br />
We show that the synthetic oleanane triterpenoid, CDDO-methyl ester (CDDO-Me;
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate) is an effective agent for
suppressing angiogenesis, both in cell culture and in vivo. The potency of
CDDO-Me is particularly striking when dosed in vivo to inhibit the angiogenic
effects of vascular endothelial growth factor and tumor necrosis factor-alpha in
Matrigel sponge assays; activity is seen at i.p. doses of CDDO-Me as low as 0.003
mg/kg of body weight. If the Matrigel sponges are impregnated with CDDO-Me just
before implantation in the mice, picomolar doses of CDDO-Me will suppress
angiogenesis. CDDO-Me also inhibits growth of endothelial cells in monolayer
cultures and suppresses neovascular morphogenesis in three-dimensional cultures,
but significantly higher doses (50-200 nmol/L) are required. We also show
antiangiogenic effects of CDDO-Me on xenografts of Kaposi/’s sarcoma cells in
immunocompromised mice, using CD31 as a marker. Several known individual
molecular targets of CDDO-Me and related triterpenoids that are relevant to all
of these findings include nuclear factor-kappaB signaling, signal transducers and
activators of transcription signaling, and transforming growth factor-beta
signaling, as well as Keap1, the endogenous inhibitor of the transcription factor
Nrf2. However, the particularly potent antiangiogenic activity seen in vivo in
the present experiments suggest that CDDO-Me, as an angioprevention agent, may be
interacting with an entire network of molecular and cellular targets, rather than
at a single molecular locus or in a single-cell type.
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