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Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer
Abstract
Synthetic oleanane triterpenoids and rexinoids are two new classes of multifunctional drugs. They are neither conventional cytotoxic agents, nor are they monofunctional drugs that uniquely target single steps in signal transduction pathways. Synthetic oleanane triterpenoids have profound effects on inflammation and the redox state of cells and tissues, as well as being potent anti-proliferative and pro-apoptotic agents. Rexinoids are ligands for the nuclear receptor transcription factors known as retinoid X receptors. Both classes of agents can prevent and treat cancer in experimental animals. These drugs have unique molecular and cellular mechanisms of action and might prove to be synergistic with standard anti-cancer treatments.
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“Synthetic triterpenoids (TP), analogues of oleanolic acid, are powerful inhibitors of oxidative stress and cellular inflammatory processes, and thus may be neuroprotective in neurodegeneration.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [181]
In the citing paper
“Synthetic TP compounds are potent inducers of the antioxidant response element (ARE)–Nrf2–Keap1 signaling pathway and are useful in a variety of the cancers including leukemia, multiple myeloma, osteosarcoma, breast and lung cancer181.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [181]
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“Since CDDO-Im can affect both Nrf2-dependent and independent pathways [37], we asked whether CDDO-Im would dampen inflammation in Nrf22/2 mice.”
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“This reaction activates the phase 2 responses, an intrinsic mechanism used by cells to deactivate electrophiles or oxidative stress [12].”
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“Triterpenes have a diverse range of biological activities and are an important source of pharmaceuticals and other commercially valuable compounds (Francis et al., 2002; Sparg et al., 2004; Liby et al., 2007).”
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“Two potent Nrf2 activators including oltipraz, a synthetic dithiothione, and methyl-2-cyano-3, 12-dioxooleana-1,9-diene-28-oate (CDDO-Me), a synthetic triterpenoid, are currently under clinical trials for cancer therapy [95,96].”
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript We also found that in skeletal muscle, after CDDO-TFEA administration, the mRNA levels of the following genes were significantly increased as compared to control diet: GST3a (Figure 6C; Fisher's PLSD, p=0.007 at 100mg/kg diet, p=0.0001…”
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“Synthetic triterpenoids (TP) such as 2-cyano-3-,12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO) and its derivatives are potent activators of the Nrf2/ARE pathway (8, 22, 23, 49).”
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“One triterpinoid, oleanolic acid, with chemical modification, can have its intrinsic anti-inflammatory activity enhanced many thousand-fold (Liby et al., 2007).”
BackgroundInfluentialSalvador, J. A. R., Leal, A. S., Valdeira, A. S. C., Gonçalves, B. M. F., Alho, D. P. S., Figueiredo, S. A. C., Silvestre, S., & Mendes, V. I. S. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.07.013 · Cited by 160
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“How can BARD have such multiple effects, on Nrf2, PPAR , and HO-1 in endothelia, epithelia, and also leukocytes? Indeed, such multiple effects were the goal of the original producers of BARD, who were aiming to develop a new class of pharmaceuticals that modulate regulatory physiological networks, rather than specific…”
BackgroundUsing the Heat-Shock Response To Discover Anticancer Compounds that Target Protein Homeostasis
Santagata, S., Xu, Y.-M., Wijeratne, E. M. K., Kontnik, R., Rooney, C., Perley, C. C., Kwon, H., Clardy, J., Kesari, S., Whitesell, L. J., et al. (2011) · ACS Chemical Biology · doi:10.1021/cb200353m · Cited by 150
Modulation of RXR function through ligand design
Pérez, E., Bourguet, W., Gronemeyer, H., & de Lera, A. R. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.04.003 · Cited by 169
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“We used the triterpenoid derivative, CDDO-Me [29], a synthetic triterpenoid that activates Nrf2 and attenuates LPS-induced inflammation in human peripheral blood mononuclear cells [31].”
Self-citationModulators of the structural dynamics of the retinoid X receptor to reveal receptor function
Nahoum, V., Pérez‐Santín, E., Germain, P., Rodríguez‐Barrios, F., Manzo, F., Kammerer, S., Lemaire, G., Hirsch, O., Royer, C. A., Gronemeyer, H., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705356104 · Cited by 143
The rise of operon-like gene clusters in plants
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Transcriptional Regulation of the AP-1 and Nrf2 Target Gene Sulfiredoxin
Soriano, F. X., Baxter, P. S., Murray, L. M., Sporn, M. B., Gillingwater, T. H., & Hardingham, G. E. (2009) · Molecules and Cells · doi:10.1007/s10059-009-0050-y · Cited by 145
“, 2007)), derivatives of which have been found to have potent cytoprotective, chemopreventive and anti-inflammatory effects (Liby et al., 2007).”
Self-citationBernstein, S. H., Venkatesh, S., Li, M., Lee, J., Lü, B., Hilchey, S. P., Morse, K. M., Metcalfe, H. M., Skalska, J., Andreeff, M., et al. (2012) · Blood · doi:10.1182/blood-2011-02-340075 · Cited by 137
Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction
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Turpaev, K. T. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913020016 · Cited by 135
The Nrf2 pathway in the progression of renal disease
Zoja, C., Benigni, A., & Remuzzi, G. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft224 · Cited by 135
“There are other molecules, including the triterpenoid CDDO-ethyl amide or RTA 405 [41], with a similar targetbased activity and the same site relative to bardoxolone methyl, but devoid of the major adverse rodent metabolism.”
BackgroundNano-enhanced immunotherapy: Targeting the immunosuppressive tumor microenvironment
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“Thus, it seems that CDDO-Me induces ER stress through depletion of intracellular GSH.”
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“…derivatives inhibit proliferation and induce apoptosis of various cancer cells in vitro and demonstrate cancer preventive or antitumor efficacy in animal models of blood, breast, colon, connective tissue, liver, lung, pancreas, prostate, and skin cancers (Liby et al. 2007; Liby and Sporn 2012).”
BackgroundInfluentialJuknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Gao, F., Coppola, G., Geschwind, D. H., & Vogel, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061462 · Cited by 121
“Our present results show that CBD, and less so THC, have immunosuppressive and protective activities that are reminiscent of other clinically applied drugs such as glucocorticoids (GCs; [74]), rexinoids and synthetic triterpenoids [75].”
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“The triterpenoids, synthesized in many plants by the cyclization of squalene, are widely used in Asian medicine [7].”
BackgroundChesney, J. A., Mitchell, R. A., & Yaddanapudi, K. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5vmr1116-458rrr · Cited by 120
“STAT3 (activated by IL-6), STAT1 (activated by IFN-g stimulation), and STAT6 [activated by CD124 (IL-4Ra)] are among the transcription factors that regulate the suppressive activity of MDSCs [70–73].”
BackgroundInfluentialDumont, M., Wille, E. J., Calingasan, N. Y., Tampellini, D., Williams, C. R., Gouras, G. K., Liby, K. T., Sporn, M. B., Beal, M. F., & Lin, M. T. S. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05970.x · Cited by 112
“Synthetic triterpenoids (TPs), derivatives of 2-cyano-3,12-dioxooleana1,9-dien-28-oic acid (CDDO), have been found to be potent inducers of nuclear factor-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling (Liby et al. 2005, 2007).”
BackgroundSelf-citationSeaweed Secondary Metabolites In Vitro and In Vivo Anticancer Activity
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“Epidemiological and experimental studies suggest that terpenoids may be helpful to curb the growth of a variety of cancer cells, including mammary, skin, lung, forestomach, colon, pancreatic and prostate carcinomas cells and open more opportunities for cancer therapy [30,31].”
BackgroundAn Exceptionally Potent Inducer of Cytoprotective Enzymes
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Pareek, T. K., Belkadi, A., Kesavapany, S., Zaremba, A., Loh, S. L., Bai, L., Cohen, M. L., Meyer, C. J., Liby, K. T., Miller, R. H., et al. (2011) · Scientific Reports · doi:10.1038/srep00201 · Cited by 107
“Further derivatization of CDDO to yield an imidazolide (CDDO-Im), an ethyl amide, (CDDO-EA), or a trifluoroethyl amide (CDDO-TFEA), resulted in significantly increased biological activit”
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“The genetic complexity of cancers suggests the use of novel multifunctional rather than monofunctional preventive or treatment agents (Liby et al., 2007).”
BackgroundChemoprevention of lung carcinogenesis in addicted smokers and ex-smokers
Hecht, S. S., Kassie, F., & Hatsukami, D. K. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2674 · Cited by 104
“Sporn, Gribble and co-workers have targeted inflammation with diverse structural analogues that inhibit inducible nitric oxide synthase and COX2 and are also phase II enzyme inducer”
BackgroundTherapeutic approaches to mitochondrial dysfunction in Parkinson's disease
Beal, M. F. (2009) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(09)70812-0 · Cited by 104
“Synthetic TP compounds are potent inducers of the antioxidant response element (ARE)/Nrf2/Keap1 signaling pathway [41].”
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“The synthetic oleanane triterpenoids activate the phase II response of cells at low nanomolar concentrations and thereby protect against oxidative stress by decreasing levels of reactive oxygen species (1).”
BackgroundYamai, H., Sawada, N., Yoshida, T., Seike, J., Takizawa, H., Kenzaki, K., Miyoshi, T., Kondo, K., Bando, Y., Ohnishi, Y., et al. (2009) · International Journal of Cancer · doi:10.1002/ijc.24433 · Cited by 101
Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease
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Metadata
- Authors
- Liby, K. T., Yore, M. M., & Sporn, M. B.
- Affiliations
- Dartmouth College (US)
- Corresponding author
- Sporn, Michael B.
- ORCID
- Liby, Karen T.
- Venue
- Nature Reviews Cancer
- Published
- 2007-04-19
- Volume
- 7
- Issue
- 5
- Pages
- 357-369
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2000178617
- Cited by
- 637
- References
- 175
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 23 · 2023: 30 · 2022: 32 · 2021: 23 · 2020: 28 · 2019: 27 · 2018: 15 · 2017: 35 · 2016: 36 · 2015: 44 · 2014: 47 · 2013: 43 · 2012: 48
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Natural product bioactivities and synthesis
- Physical Sciences › Chemistry › Organic Chemistry › Phytochemical Studies and Bioactivities
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Effects of Natural Compounds
- Keywords
- oleanane triterpenoids, rexinoids, cancer prevention, cancer therapy, retinoid X receptor, antiproliferative agents, apoptosis, inflammation, redox state, multi-target drugs, drug synergy
- MeSH terms
- Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Dose-Response Relationship, Drug, Humans, Neoplasms, Oleanolic Acid, Anticarcinogenic Agents, Retinoid X Receptors, Mice
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