The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice.

LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate.

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.

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.

The PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice.

Poly-ADP ribose polymerase (PARP) inhibitors are effective for the treatment of BRCA-deficient tumors. Women with these mutations have an increased risk of developing breast cancer and would benefit from effective chemoprevention. This study examines whether the PARP inhibitors, veliparib and olaparib, delay mammary gland tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model.

The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer.

Novel drugs and drug combinations are needed for the chemoprevention and treatment of cancer. We show that the histone deacetylase inhibitor vorinostat [suberoylanilide hydroxamic acid (SAHA)] and the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me and CDDO-Ea, respectively) cooperated to inhibit the de novo synthesis of nitric oxide in RAW 264.7 macrophage-like cells and in primary mouse peritoneal macrophages.

The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice.

Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor-negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis.

CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice.

The breast cancer-associated gene 1 (BRCA1) is the most frequently mutated tumor suppressor gene in familial breast cancers. Mutations in BRCA1 also predispose to other types of cancers, pointing to a fundamental role of this pathway in tumor suppression and emphasizing the need for effective chemoprevention in these high-risk patients. Because the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) is a potent chemopreventive agent, we tested its efficacy in a highly relevant mouse model of BRCA1-mutated breast cancer.

Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly always fatal. Whereas early detection offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and rexinoids, for the prevention of carcinogenesis in the highly relevant LSL-Kras(G12D/+);LSL-Trp53(R127H/+);Pdx-1-Cre (KPC) mouse model of pancreatic cancer.

Triterpenoids CDDO-methyl ester or CDDO-ethyl amide and rexinoids LG100268 or NRX194204 for prevention and treatment of lung cancer in mice.

We tested members of two noncytotoxic classes of drugs, synthetic oleanane triterpenoids and rexinoids, both as individual agents and in combination, for the prevention and treatment of carcinogenesis in a highly relevant animal model of lung cancer. Lung adenocarcinomas were induced in A/J mice by injection of the carcinogen vinyl carbamate. Mice were fed drugs in diet, beginning 1 week after the carcinogen challenge for prevention or 8 weeks later for treatment.

Neuroprotective effects of the triterpenoid, CDDO methyl amide, a potent inducer of Nrf2-mediated transcription.

The NF-E2-related factor-2 (Nrf2)/antioxidant response element (ARE) signaling pathway regulates phase 2 detoxification genes, including a variety of antioxidative enzymes. We tested neuroprotective effects of the synthetic triterpenoid CDDO-MA, a potent activator of the Nrf2/ARE signaling. CDDO-MA treatment of neuroblastoma SH-SY5Y cells resulted in Nrf2 upregulation and translocation from cytosol to nucleus and subsequent activation of ARE pathway genes.

A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin.

A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, inducible nitric oxide synthase, activate phase 2 cytoprotective enzymes in vitro and in vivo, block cell proliferation, and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced preneoplastic hepatic lesions in rats by >90%.

Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268.

Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)-negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice.

Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks.

The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis.

Female A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks.

A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland.

Purpose: We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)-negative breast cancer in vivo.

Experimental Design: In cell culture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogen vinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen.

The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice.

We report the first use of new synthetic triterpenoids to prevent lung cancer in experimental animals. Female A/J mice were treated with the mutagenic carcinogen vinyl carbamate, which induces adenocarcinoma of the lung in all animals within 16 weeks. If mice were fed either the methyl ester or the ethyl amide derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-ME and CDDO-EA, respectively), beginning 1 week after dosing with carcinogen, the number, size, and severity of lung carcinomas were markedly reduced.

The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor-negative model of breast cancer.

Purpose: We tested whether a selective estrogen receptor modulator (SERM) and a rexinoid are active for prevention and treatment in the mouse mammary tumor virus-neu mouse model of estrogen receptor-negative breast cancer.

Experimental Design: For prevention, mice were fed a powdered control diet, the SERM arzoxifene (Arz, 20 mg/kg diet), the rexinoid LG100268 (268, 30 mg/kg diet), or the combination for 60 weeks. In a second prevention study, mice were fed Arz (6 mg/kg diet), 268 (30 mg/kg diet), the combination of Arz and 268, the SERM acolbifene (Acol, 3 mg/kg diet), or the combination of Acol and 268 for 52 weeks.

Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A.

Fifteen new betulinic acid analogues were designed, synthesized, and tested for anti-inflammatory activity. Many of these analogues effectively suppress nitric oxide (NO) production in RAW cells stimulated with interferon-gamma. Analogue 10 is highly and orally active in vivo for induction of the anti-inflammatory and cytoprotective enzyme, heme oxygenase-1.

The synthetic triterpenoid CDDO-Imidazolide suppresses STAT phosphorylation and induces apoptosis in myeloma and lung cancer cells.

Purpose: Excessive activity of the transcription factors known as signal transducers and activators of transcription (STAT) contributes to the development and progression of malignancy in many organs. It is, therefore, important to develop new drugs to control the STATs, particularly their phosphorylation state, which is required for their transcriptional activity.

Experimental Design: Myeloma and lung cancer cells were treated with the new synthetic triterpenoid CDDO-Imidazolide, and STAT phosphorylation and apoptosis were evaluated by immunoblotting and fluorescence-activated cell sorting analysis.

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.

Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress.

A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-gamma of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g.

The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor beta-dependent apoptosis in breast cancer.

We show that the selective estrogen receptor modulator arzoxifene (Arz) and the rexinoid LG100268 (268) synergize to promote apoptosis in a rat model of estrogen receptor-positive breast carcinoma and in estrogen receptor-positive human breast cancer cells in culture. We also show that it is not necessary to administer Arz and 268 continuously during tumor progression to prevent cancer in the rat model because dosing of these drugs in combination for relatively short periods, each followed by drug-free rests, is highly effective. This new approach to chemoprevention uses high doses of drugs that are too toxic for long-term administration.

The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo.

1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a novel synthetic triterpenoid more potent than its parent compound, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), both in vitro and in vivo. CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines (IC(50), approximately 10-30 nM). In U937 leukemia cells, CDDO-Im also induces monocytic differentiation as measured by increased cell surface expression of CD11b and CD36.

Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling.

We have studied the effects of two new synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivative, 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole (CDDO-Im), on transforming growth factor (TGF)-beta/Smad signaling. These agents, at nanomolar concentrations, increase the expression of TGF-beta-dependent genes, such as those for plasminogen activator inhibitor 1 and the type II TGF-beta receptor, and they synergize with TGF-beta in this regard. They prolong the activation of Smad2 induced by TGF-beta and markedly enhance the ability of Smad3 to activate a Smad binding element, CAGA-luciferase.

Design and synthesis of tricyclic compounds with enone functionalities in rings A and C: a novel class of highly active inhibitors of nitric oxide production in mouse macrophages.

Novel tricyclic compounds with enone functionalities in rings A and C, which were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid, have been synthesized. Among them, 10 shows high inhibitory activity (IC(50) = 1 nM level) against production of nitric oxide induced by interferon-gamma in mouse macrophages and is orally active at 15 mg/kg (once) in a preliminary in vivo study using mouse peritoneal inflammation induced by thioglycollate and interferon-gamma.