A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice

Dinkova‐Kostova, Albena T.; Jenkins, Stephanie N.; Wehage, Scott L.; Huso, David L.; Benedict, Andrea L.; Stephenson, Katherine K.; Fahey, Jed W.; Liu, Hua; Liby, Karen T.; Honda, Tadashi; Gribble, Gordon W.; Sporn, Michael B.; Talalay, Paul

doi:10.1016/j.bbrc.2008.01.026

Cited by 15 publications

(10 citation statements)

References 23 publications

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“…In SKH-1 hairless mice exposed to chronic low-level UBV radiation for 17 weeks and then treated topically with di-CDDO (TP-225), skin tumor multiplicity is 50% lower and total tumor burden is 5-fold lower in the mice treated with diCDDO compared with the controls. This SO also increases NQO1 and HO-1 cytoprotective enzyme activity in the skin of these "high risk" hairless mice (Dinkova-Kostova et al, 2008). The SOs are also potent inhibitors of lung carcinogenesis in A/J mice.…”

Section: Other Diseasesmentioning

confidence: 87%

“…With the exception of the aflatoxin studies (Yates et al, 2006), the SOs were not administered until at least 1 week after challenge with a carcinogen, suggesting that the SOs were not simply preventing cancer by detoxifying the original insult before it could initiate DNA damage. The Nrf2/ARE pathway was important for prevention of carcinogenesis by the SOs in the liver (Yates et al, 2006) and skin (Dinkova-Kostova et al, 2008), but there is no evidence that this pathway is required for efficacy in the other prevention studies. In fact, several recent studies suggest that activation of the Nrf2/ARE pathway in cancer cells may be detrimental and contribute to resistance to chemotherapy or radiation (Taguchi et al, 2011).…”

Section: Other Diseasesmentioning

confidence: 99%

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Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

2012

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Section: Other Diseasesmentioning

confidence: 87%

Section: Other Diseasesmentioning

confidence: 99%

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

2012

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“…We have previously demonstrated the chemopreventive efficacy of TP-225 in SKH-1 hairless mice exposed to ultraviolet B radiation, in which topical application of the compound was shown to stimulate Nrf2 signaling and reduce the appearance of premalignant lesions and the volume of malignant tumors (Dinkova-Kostova et al. , 2008). Despite these promising properties, the development of TP-225 as a therapeutic agent has been hindered by its poor oral bioavailability (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Chemical Tuning Enhances Both Potency Toward Nrf2 and In Vitro Therapeutic Index of Triterpenoids

Copple

Shelton

Walsh

et al. 2014

Toxicological Sciences

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The transcription factor Nrf2 protects against a number of experimental pathologies, and is a promising therapeutic target. The clinical investigation of a potent Nrf2-inducing agent, the triterpenoid (TP) bardoxolone methyl (BARD), was recently halted due to adverse cardiovascular events in chronic kidney disease patients, although the underlying mechanisms are yet to be resolved. The majority of small molecule Nrf2 inducers are electrophilic and trigger Nrf2 accumulation via the chemical modification of its redox-sensitive repressor Keap1. Therefore, it is pertinent to question whether the therapeutic targeting of Nrf2 could be hindered in many cases by the inherent reactivity of a small molecule inducer toward unintended cellular targets, a key mechanism of drug toxicity. Using H4IIE-ARE8L hepatoma cells, we have examined the relationship between (a) Nrf2 induction potency, (b) toxicity and (c) in vitro therapeutic index (ratio of b:a) for BARD and a number of other small molecule activators of Nrf2. We show that BARD exhibits the highest potency toward Nrf2 and the largest in vitro therapeutic index among compounds that have been investigated clinically (namely BARD, sulforaphane and dimethylfumarate). Through further examination of structurally related TPs, we demonstrate that an increase in potency toward Nrf2 is associated with a relatively smaller increase in toxicity, indicating that medicinal chemistry can be used to enhance the specificity of a compound as an inducer of Nrf2 signaling whilst simultaneously increasing its therapeutic index. These findings will inform the continuing design and development of drugs targeting Nrf2.

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“…Treatment with an NQO1 inhibitor dicoumarol reversed the protective effect of oltipraz in this model (28). Topical application of a synthetic triterpenoid, oleanane dicyanotriterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225), to SKH-1 hairless mice increased the levels of NQO1 and HO-1 and protected against UV-radiation-induced skin inflammation and tumor promotion (29). Likewise, induction of HO-1 in the colonic tissue by administering cobalt protoporphyrin (CoPP) attenuated acute dextran sulfate sodium (DSS)-induced mouse colitis with a concomitant reduction of interferon (IFN)-gamma production.…”

Section: Roles Of Antioxidant and Cytoprotective Enzymes In Chemoprevmentioning

confidence: 99%

Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis

2010

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Persistent inflammatory tissue damage is causally associated with each stage of carcinogenesis. Inflammation-induced generation of reactive oxygen species, reactive nitrogen species, and other reactive species not only cause DNA damage and subsequently mutations, but also stimulate proliferation of initiated cells and even metastasis and angiogenesis. Induction of cellular cytoprotective enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase, superoxide dismutase, glutathione-S-transferase, etc.) has been shown to mitigate aforementioned events implicated in inflammation-induced carcinogenesis. A unique feature of genes encoding these cytoprotective enzymes is the presence of a cis-acting element, known as antioxidant response element (ARE) or electrophile response element (EpRE), in their promoter region. A stress-responsive transcription factor, nuclear factor erythroid-2-related factor-2 (Nrf2), initially recognized as a key transcriptional regulator of various cytoprotective enzymes, is known to play a pivotal role in cellular defense against inflammatory injuries. Activation of Nrf2 involves its release from the cytosolic repressor Kelch-like ECH-associated protein-1 (Keap1) and subsequent stabilization and nuclear localization for ARE/EpRE binding. Genetic or pharmacologic inactivation of Nrf2 has been shown to abolish cytoprotective capability and to aggravate experimentally induced inflammatory injuries. Thus, Nrf2-mediated cytoprotective gene induction is an effective strategy for the chemoprevention of inflammation-associated carcinogenesis.

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A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice

Cited by 15 publications

References 23 publications

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

Chemical Tuning Enhances Both Potency Toward Nrf2 and In Vitro Therapeutic Index of Triterpenoids

Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis

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