Novel synthetic oleanane triterpenoids: A series of highly active inhibitors of nitric oxide production in mouse macrophages

Honda, T.; Rounds, BarbieAnn V.; Bore, Lothar; Favaloro, Frank G.; Gribble, Gordon W.; Suh, Nanjoo; Wang, Yongping; Sporn, Michael B.

doi:10.1016/s0960-894x(99)00623-x

Cited by 66 publications

(50 citation statements)

References 10 publications

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“…1). This is in agreement with other reports showing greater toxicity of CDDO-Im compared to CDDO [7,10,18] and others showing greater effect of CDDO-Im on the intracellular molecular targets compared to CDDO [33,34]. Our results are also consistent with others showing a similar role for synthetic triterpenoids in primary CLL cells [20], primary multiple myeloma cells [18] and primary promyelotic leukemia cells [32].…”

Section: Discussionsupporting

confidence: 93%

CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia

et al. 2008

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Waldenström macroglobulinemia (WM) is a B-cell malignancy that remains incurable. Synthetic triterpenoids (ST), 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), its methyl ester derivative (CDDO-Me) and imidazolide derivative (CDDO-Im) induce cell death and inhibit growth of various malignancies and hold promise as treatment for cancer patients. We examined the therapeutic potential of these compounds in WM. All three forms of CDDO induced equal toxicity in BCWM.1 cells. In malignant B cells from WM patients, CDDO-Im induced the greatest toxicity. CDDO-Im inhibited proliferation at nanomolar concentrations and arrested the cells in G0/G1. CDDO-Im induced apoptotic cell death that was partially abolished in the presence of caspase inhibitor. CDDO-Im also inhibited survival pathways that have been shown to be important in WM. Overall, our data suggest that ST are likely to provide therapeutic efficacy for WM patients.

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Section: Discussionsupporting

confidence: 93%

CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia

et al. 2008

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“…Many of the plant-derived triterpenoids are considered weak anti-inflammatory and/or anticancer agents, which has encouraged the identification of novel synthetic analogues with greater potency (2). One such analogue, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 1 has gained recognition as a promising cancer chemopreventive and therapeutic agent (3).…”

Section: ؉mentioning

confidence: 99%

“…One such analogue, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 1 has gained recognition as a promising cancer chemopreventive and therapeutic agent (3). In vitro studies have shown that nanomolar concentrations of CDDO can inhibit the proliferation of various human tumor cell types (3,4), suppress the activity of inflammatory cytokines such as interferon-␥, interleukin-1, and tumor necrosis factor (2,3), and inhibit the induction of inflammatory mediators such as cyclooxygenase-2 and nitric oxide synthase (2,3). More recently, low micromolar concentrations (Յ10 M) of CDDO have been shown to induce apoptosis in human myeloid (5,6) and lymphocytic leukemia cells (7), osteosarcoma cells (8), and breast cancer cells (4).…”

Section: ؉mentioning

confidence: 99%

“…CDDO was synthesized by Dr. Tadashi Honda (Dartmouth Medical School, Hanover, NH) as described previously (2) and provided by Dr. Edward Sausville (Developmental Therapeutics Program, NCI, Bethesda, MD) through the Rapid Access to Intervention Development (RAID) Program. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) was obtained from Dr. Ronald Lubet (Division of Cancer Prevention and Control, NCI, Bethesda, MD).…”

Section: ؉mentioning

confidence: 99%

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Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Hail

Konopleva

Sporn

et al. 2004

Journal of Biological Chemistry

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The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel anticancer agent that induces apoptosis in tumor cells. The cytotoxic stress underpinning CDDO-induced apoptosis has not been established. This study compared and contrasted the effects of CDDO on COLO 16 human skin cancer cells and their respiration-deficient ( 0 ) clones to elucidate the stress signal responsible for initiating apoptosis. CDDO promoted apoptosis in COLO 16 cells in a doseand time-dependent manner. The 0 clones appeared to be more sensitive to CDDO-induced apoptosis implying that the disruption of mitochondrial respiration was not directly associated with triggering cell death. After a 4-h exposure to CDDO, mitochondrial inner transmembrane potential-sensitive dyes revealed mitochondrial hyperpolarization in the COLO 16 cells and mitochondrial depolarization in the 0 clones. Electron microscopy illustrated that this exposure also promoted mitochondrial condensation, endoplasmic reticulum dilation, and chromatin condensation in the COLO 16 cells. Endoplasmic reticulum dilation and chromatin condensation were also observed in the 0 clones, but the mitochondria in these cells were markedly swollen implying that the disruption of intracellular Ca 2؉ homeostasis was associated with cell death. A Ca 2؉ -sensitive dye confirmed that CDDO increased cytoplasmic free Ca Triterpenoids derived from plants are used for medicinal purposes in many Asian countries and have been reported to have anticancer activity (1). Many of the plant-derived triterpenoids are considered weak anti-inflammatory and/or anticancer agents, which has encouraged the identification of novel synthetic analogues with greater potency (2). One such analogue, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 1 has gained recognition as a promising cancer chemopreventive and therapeutic agent (3). In vitro studies have shown that nanomolar concentrations of CDDO can inhibit the proliferation of various human tumor cell types (3, 4), suppress the activity of inflammatory cytokines such as interferon-␥, interleukin-1, and tumor necrosis factor (2, 3), and inhibit the induction of inflammatory mediators such as cyclooxygenase-2 and nitric oxide synthase (2, 3). More recently, low micromolar concentrations (Յ10 M) of CDDO have been shown to induce apoptosis in human myeloid (5, 6) and lymphocytic leukemia cells (7), osteosarcoma cells (8), and breast cancer cells (4).Apoptosis is the mechanism utilized by metazoans to eliminate redundant or potentially deleterious cells and is considered an essential process for regulating tissue homeostasis. Apoptosis induction is arguably the most potent defense against cancer making it a desirable end point for both chemoprevention (9) and chemotherapy (10). Apoptosis is a relatively linear process. It is triggered by an initiation phase that is highly varied depending on cell type and the underlying stress stimulus (e.g. oxidative stress, DNA damage, ion fluctuations, and cytokines). This is followed by an effe...

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“…Inducers are also antiinflammatory agents, and there is a linear correlation between these two biologic activities that spans 6 orders of magnitude of inducer concentrations (7,8). Semisynthetic pentacyclic triterpenoids (9)(10)(11) and related synthetic tricyclic compounds (12)(13)(14)(15) which contain Michael acceptors are the most potent inducers known to date, activating Nrf2 and inhibiting proinflammatory responses at sub-to low nanomolar concentrations (7,16,17). Furthermore, they show remarkable protective efficacy in a number of preclinical animal models of chronic disease, including carcinogenesis, cardiovascular disease, and neurodegeneration, and in early clinical trials (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

Kalra

Knatko

Zhang

et al. 2012

Cancer Prevention Research

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Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation-induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility. Cancer Prev Res; 5(7); 973-81. Ó2012 AACR.

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Novel synthetic oleanane triterpenoids: A series of highly active inhibitors of nitric oxide production in mouse macrophages

Cited by 66 publications

References 10 publications

CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia

CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

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