共查询到20条相似文献,搜索用时 15 毫秒
1.
Honda T Rounds BV Bore L Favaloro FG Gribble GW Suh N Wang Y Spor MB 《Bioorganic & medicinal chemistry letters》1999,9(24):757-3434
Novel oleanane triterpenoids with modified rings A and C were designed and synthesized. Among them, methyl 2-carboxy-3,12-dioxooleana-1,9-dien-28-oate showed similar high inhibitory activity (IC50 = 0.8 nM) to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), which we have synthesized previously, against production of nitric oxide induced by interferon-γ in mouse macrophages. 相似文献
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Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179 总被引:3,自引:0,他引:3
Ahmad R Raina D Meyer C Kharbanda S Kufe D 《The Journal of biological chemistry》2006,281(47):35764-35769
The novel oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) and the C-28 methyl ester (CDDO-Me) induce apoptosis of human tumor cells by disruption of redox balance and are currently in clinical trials. The present studies show that CDDO and CDDO-Me block tumor necrosis factoralpha-induced targeting of NF-kappaB p65 to the nucleus. CDDO-Me also blocked tumor necrosis factor alpha-induced phosphorylation of IkappaBalpha. In concert with these results, we found that CDDO-Me inhibits IkappaBalpha kinasebeta (IKKbeta) activity in cells. In support of a direct mechanism, CDDO-Me inhibited recombinant IKKbeta activity in vitro. The results also demonstrate that (i) CDDO and CDDO-Me form adducts with IKKbeta, but not IKKbeta with mutation of Cys-179 to Ala, and (ii) CDDO-Me inhibits IKKbeta by a mechanism dependent on oxidation of Cys-179. These findings indicate that CDDO and CDDO-Me directly block IKKbeta activity and thereby the NF-kappaB pathway by interacting with Cys-179 in the IKKbeta activation loop. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(2):532-534
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO, 2) was condensed with various amino acid methyl esters at the C-28 carboxylic acid. The new amide conjugates were evaluated for their inhibition of nitric oxide (NO) production in RAW264.7 cells stimulated with interferon-γ (IFNγ). Of these new compounds, CDDO conjugates with alanine, valine, and serine are nearly equipotent to CDDO-ethyl amide (4), a triterpenoid with promising biological activity in numerous disease models. Some of these conjugates also induce the in vitro expression of heme oxygenase-1, and inhibit the proliferation of Panc-1343 pancreatic cells. 相似文献
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Ikeda T Kimura F Nakata Y Sato K Ogura K Motoyoshi K Sporn M Kufe D 《Cell death and differentiation》2005,12(5):523-531
The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of diverse human tumor cells. In the present study, we examined the effects of the CDDO imidazolide imide (CDDO-Im) on the NB4 acute promyelocytic leukemia (APL) cell line and primary APL cells. The results show that CDDO-Im selectively downregulates expression of the PML/retinoic receptor alpha fusion protein by a caspase-dependent mechanism and sensitizes APL cells to the differentiating effects of all-trans retinoic acid (ATRA). CDDO-Im treatment of APL cells was also associated with disruption of redox balance and activation of the extrinsic apoptotic pathway. In concert with these results, CDDO-Im sensitizes APL cells to arsenic trioxide (ATO)-induced apoptosis. Our findings indicate that CDDO-Im may be effective in the treatment of APL by: (i) downregulation of PML/RARalpha; (ii) enhancement of ATRA-induced differentiation; and (iii) sensitization of ATO-induced APL cell death. 相似文献
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Tadashi Honda Eric M. Padegimas Emilie David Chitra Sundararajan Karen T. Liby Charlotte Williams Michael B. Sporn Melean Visnick 《Bioorganic & medicinal chemistry letters》2010,20(7):2275-2278
2-Cyano-3,10-dioxooleana-1,9(11)-dien-28-oic acid anhydride (CDDO anhydride) has been synthesized, which is the first example of an oleanane triterpenoid anhydride. CDDO anhydride shows potency similar to or higher than the corresponding acid (CDDO) in various in vitro and in vivo assays related to inflammation and carcinogenesis. Notably, preliminary phamacokinetics studies show that CDDO anhydride levels are higher than CDDO levels in mouse tissues and blood. Further evaluation of CDDO anhydride is in progress. 相似文献
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Ciric To Brian H. Shilton Gianni M. Di Guglielmo 《The Journal of biological chemistry》2010,285(36):27944-27957
Synthetic triterpenoids are anti-tumor agents that affect numerous cellular functions including apoptosis and growth inhibition. Here, we used mass spectrometric and protein array approaches and uncovered that triterpenoids associate with proteins of the actin cytoskeleton, including actin-related protein 3 (Arp3). Arp3, a subunit of the Arp2/3 complex, is involved in branched actin polymerization and the formation of lamellipodia. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-Im and CDDO-Me were observed to 1) inhibit the localization of Arp3 and actin at the leading edge of cells, 2) abrogate cell polarity, and 3) inhibit Arp2/3-dependent branched actin polymerization. We confirmed our drug effects with siRNA targeting of Arp3 and observed a decrease in Rat2 cell migration. Taken together, our data suggest that synthetic triterpenoids target Arp3 and branched actin polymerization to inhibit cell migration. 相似文献
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Jae Lee Ashutosh K. Pandey Sundararajan Venkatesh Jayapalraja Thilagavathi Tadashi Honda Kamal Singh Carolyn K. Suzuki 《The Journal of biological chemistry》2022,298(3)
The mitochondrial protein LonP1 is an ATP-dependent protease that mitigates cell stress and calibrates mitochondrial metabolism and energetics. Biallelic mutations in the LONP1 gene are known to cause a broad spectrum of diseases, and LonP1 dysregulation is also implicated in cancer and age-related disorders. Despite the importance of LonP1 in health and disease, specific inhibitors of this protease are unknown. Here, we demonstrate that 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its -methyl and -imidazole derivatives reversibly inhibit LonP1 by a noncompetitive mechanism, blocking ATP-hydrolysis and thus proteolysis. By contrast, we found that CDDO-anhydride inhibits the LonP1 ATPase competitively. Docking of CDDO derivatives in the cryo-EM structure of LonP1 shows these compounds bind a hydrophobic pocket adjacent to the ATP-binding site. The binding site of CDDO derivatives was validated by amino acid substitutions that increased LonP1 inhibition and also by a pathogenic mutation that causes cerebral, ocular, dental, auricular and skeletal (CODAS) syndrome, which ablated inhibition. CDDO failed to inhibit the ATPase activity of the purified 26S proteasome, which like LonP1 belongs to the AAA+ superfamily of ATPases Associated with diverse cellular Activities, suggesting that CDDO shows selectivity within this family of ATPases. Furthermore, we show that noncytotoxic concentrations of CDDO derivatives in cultured cells inhibited LonP1, but not the 26S proteasome. Taken together, these findings provide insights for future development of LonP1-specific inhibitors with chemotherapeutic potential. 相似文献
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Neymotin A Calingasan NY Wille E Naseri N Petri S Damiano M Liby KT Risingsong R Sporn M Beal MF Kiaei M 《Free radical biology & medicine》2011,51(1):88-96
Oxidative damage, neuroinflammation, and mitochondrial dysfunction contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), and these pathologic processes are tightly regulated by the Nrf2/ARE (NF-E2-related factor 2/antioxidant response element) signaling program. Therefore, modulation of the Nrf2/ARE pathway is an attractive therapeutic target for neurodegenerative diseases such as ALS. We examined two triterpenoids, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid) ethylamide and CDDO trifluoroethylamide (CDDO-TFEA), that potently activate Nrf2/ARE in a cell culture model of ALS and in the G93A SOD1 mouse model of ALS. Treatment of NSC-34 cells stably expressing mutant G93A SOD1 with CDDO-TFEA upregulated Nrf2 expression and resulted in translocation of Nrf2 into the nucleus. Western blot analysis showed an increase in the expression of Nrf2/ARE-regulated proteins. When treatment started at a “presymptomatic age” of 30 days, both of these compounds significantly attenuated weight loss, enhanced motor performance, and extended the survival of G93A SOD1 mice. Treatment started at a “symptomatic age,” as assessed by impaired motor performance, was neuroprotective and slowed disease progression. These findings provide further evidence that compounds that activate the Nrf2/ARE signaling pathway may be useful in the treatment of ALS. 相似文献
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To C Kulkarni S Pawson T Honda T Gribble GW Sporn MB Wrana JL Di Guglielmo GM 《The Journal of biological chemistry》2008,283(17):11700-11713
The anti-tumor synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO)-imidazolide (CDDO-Im) ectopically activates the transforming growth factor beta (TGFbeta)-Smad pathway and extends the duration of signaling by an undefined mechanism. Here we show that CDDO-Imdependent persistence of Smad2 phosphorylation is independent of Smad2 phosphatase activity and correlates with delayed TGFbeta receptor degradation and trafficking. Altered TGFbeta trafficking parallels the dispersal of EEA1-positive endosomes from the perinuclear region of CDDO-Im-treated cells. The effect of CDDO-Im on the EEA1 compartment led to an analysis of the cytoskeleton, and we observed that CDDO-Im alters microtubule dynamics by disrupting the microtubule-capping protein, Clip-170. Interestingly, biotinylated triterpenoid was found to localize to the polarity complex at the leading edge of migrating cells. Furthermore, CDDO-Im disrupted the localization of IQGAP1, PKCzeta, Par6, and TGFbeta receptors from the leading edge of migrating cells and inhibited TGFbeta-dependent cell migration. Thus, the synthetic triterpenoid CDDO-Im interferes with TGFbeta receptor trafficking and turnover and disrupts cell migration by severing the link between members of the polarity complex and the microtubule network. 相似文献
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Hail N Konopleva M Sporn M Lotan R Andreeff M 《The Journal of biological chemistry》2004,279(12):11179-11187
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 (rho(0)) clones to elucidate the stress signal responsible for initiating apoptosis. CDDO promoted apoptosis in COLO 16 cells in a dose- and time-dependent manner. The rho(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 rho(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 rho(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(2+) in the COLO 16 cells, their rho(0) clones, as well as in malignant breast and lung epithelial cells. A cell-permeant Ca(2+) chelator reduced the CDDO-induced increase in cytoplasmic free Ca(2+), and inhibited caspase activation, the development of apoptotic morphology, and DNA fragmentation in the COLO 16 cells, implying that Ca(2+) played a pivotal role in signaling the initiation of apoptosis. 相似文献
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Y Ito P Pandey A Place M B Sporn G W Gribble T Honda S Kharbanda D Kufe 《Cell growth & differentiation》2000,11(5):261-267
The oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multifunctional molecule that induces growth inhibition and differentiation of human myeloid leukemia cells. The present studies demonstrate that CDDO treatment results in apoptosis of U-937 and HL-60 myeloid leukemia cells. Similar to 1-beta-D-arabinofuranosylcytosine (ara-C), another agent that inhibits growth and induces apoptosis of these cells, CDDO induced the release of mitochondrial cytochrome c and activation of caspase-3. Overexpression of Bcl-X(L) blocked cytochrome c release, caspase-3 activation, and apoptosis in ara-C-treated cells. By contrast, CDDO-induced release of cytochrome c, and activation of caspase-3 were diminished only in part by Bcl-X(L). In concert with these findings, we demonstrate that CDDO, but not ara-C, activates caspase-8 and thereby caspase-3 by a cytochrome c-independent mechanism. The results also show that CDDO-induced cytochrome c release is mediated by caspase-8-dependent cleavage of Bid. These findings demonstrate that CDDO induces apoptosis of myeloid leukemia cells and that this novel agent activates an apoptotic signaling cascade distinct from that induced by the cytotoxic agent ara-C. 相似文献
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Deeb D Gao X Liu Y Kim SH Pindolia KR Arbab AS Gautam SC 《Biochemical and biophysical research communications》2012,422(4):561-567
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Stadheim TA Suh N Ganju N Sporn MB Eastman A 《The Journal of biological chemistry》2002,277(19):16448-16455
Tumor necrosis factor (TNF) is a potent activator of the nuclear factor-kappaB (NF-kappaB) pathway that leads to up-regulation of anti-apoptotic proteins. Hence, TNF induces apoptosis in the presence of inhibitors of protein or RNA synthesis. We report that a novel triterpenoid, 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO) inhibits NF-kappaB-mediated gene expression at a step after translocation of activated NF-kappaB to the nucleus. This effect appears specific for the NF-kappaB pathway as CDDO does not inhibit gene expression induced by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA). CDDO in combination with TNF caused a dramatic increase in apoptosis in ML-1 leukemia cells that was associated with activation of caspase-8, cleavage of Bid, translocation of Bax, cytochrome c release, and caspase-3 activation. Experiments with caspase inhibitors demonstrated that caspase-8 was an initiator of this pathway. TNF also induced a transient activation of c-Jun N-terminal kinase (JNK), which upon addition of CDDO was converted to a sustained activation. The activation of JNK was also dependent on caspase-8. Sustained activation of JNK is frequently pro-apoptotic, yet inhibition of JNK did not prevent Bax translocation or cytochrome c release, demonstrating its lack of involvement in CDDO/TNF-induced apoptosis. Apoptosis was acutely induced by CDDO/TNF in every leukemia cell line tested including those that overexpress Bcl-x(L), suggesting that the mitochondrial pathway is not required for apoptosis by this combination. These results suggest that the apoptotic potency of the CDDO/TNF combination occurs through selective inhibition of NF-kappaB-dependent anti-apoptotic proteins, bypassing potential mitochondrial resistance mechanisms, and thus may provide a basis for the development of novel approaches to the treatment of leukemia. 相似文献
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Dinkova-Kostova AT Jenkins SN Wehage SL Huso DL Benedict AL Stephenson KK Fahey JW Liu H Liby KT Honda T Gribble GW Sporn MB Talalay P 《Biochemical and biophysical research communications》2008,367(4):859-865
Inducible phase 2 enzymes constitute a primary line of cellular defense. The oleanane dicyanotriterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225) is a very potent inducer of these systems. Topical application of TP-225 to SKH-1 hairless mice increases the levels of NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) and protects against UV radiation-induced dermal thickening. Daily topical treatments of 10 nmol of TP-225 to the backs of mice that were previously subjected to low-level chronic UVB radiation (30 mJ/cm2/session, twice a week for 17 weeks), led to 50% reduction in multiplicity of skin tumors. In addition, the total tumor burden of squamous cell carcinomas was reduced by 5.5-fold. The identification of new agents for protection against UV radiation-induced skin cancer and understanding of their mechanism(s) of action is especially important in view of the fact that human skin cancers represent a significant source of increasing morbidity and mortality. 相似文献
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Liu Y Gao X Deeb D Gautam SC 《Biochemical and biophysical research communications》2012,417(1):570-575
Our previous studies have shown that methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me), a oleanane synthetic triterpenoid induces apoptosis in prostate cancer cells by inhibiting the Akt/NF-κB/mTOR signaling cascade; however, the mechanism by which CDDO-Me inhibits Akt/NF-κB/mTOR signaling has remained undetermined. Present studies show that Akt plays a critical role in the response of prostate cancer cells to CDDO-Me. Silencing of Akt sensitized PC-3 cells to CDDO-Me, whereas its overexpression rendered them resistant to CDDO-Me. Evaluation of the effect of CDDO-Me on Akt which lies upstream of NF-κB and mTOR showed that CDDO-Me directly inhibits the Akt kinase activity in cell-free kinase activity assay and in vivo without modulating the activity of PDK1, the upstream kinase that phosphorylates and activates Akt. The inhibition of Akt activity resulted in inhibition of phosphorylation/inactivation of proapoptotic procaspase-9, Bad and Foxo3a. Further, inhibition of p-Akt by CDDO-Me was not attributable to an increase in the activity of protein phosphatase 2A (PP2A) or PH domain/leucine-rich repeat protein phosphatase1 (PHLPP1) both of which dephosphorylate p-Akt. These findings show that Akt is a direct target of CDDO-Me in the Akt/NF-κB/mTOR prosurvival signaling axis. 相似文献