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Konopleva, Marina, Ismael Samudio, Twee Tsao, Steven M. Kornblau, Yue-Xi Shi, Teresa McQueen, Rooha Contractor, et al. "Mechanisms and Activity of PPARγ-Active Triterpenoids CDDO and CDDO-Me in Leukemias." Blood 106, no. 11 (November 16, 2005): 2460. http://dx.doi.org/10.1182/blood.v106.11.2460.2460.
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Abstract First-line therapy of acute myeloid leukemia (AML) consists of combinations of cytarabine and an anthracycline. While initial complete remissions are frequent, most patients succumb to resistant disease underlining the need for novel, more effective agents. The most striking progress in AML therapy was achieved by targeting the nuclear receptor RARα with ATRA. Research in our laboratory has demonstrated that the novel synthetic triterpenoid CDDO (2-cyano-3,12- dioxooleana-1,9-dien-28-oic acid) and its more active C28 methyl ester derivative CDDO-Me inhibit growth and induce apoptosis in a variety of cancers including AML, CLL and blast crisis CML. CDDO and to a much higher degree CDDO-Me are potent activators of the nuclear transcription factor Peroxisome Proliferator-Activated Receptor gamma (PPARγ). In a mammalian two-hybrid assay, the CDDO and CDDO-Me induced activation of PPARγ was associated with a marked increase in multiple coactivator recruitment (SRC-1, SRC-2, SRC-3, TRAP220/DRIP205, CARM-1 and PGC-1) that is qualitatively different from that induced by other PPARγ ligands. CDDO induced a higher degree of myelo-monocytic differentiation in DRIP205-overexpressing HL-60 cells suggesting that high cellular levels of DRIP205 co-activator modulate differentiation response to PPARγ ligation. CDDO induced p21 mRNA and protein in leukemic cells and transactivation of the p21 promoter in a p53-independent fashion. We have recently identified the PPARγ-independent depletion of mitochondrial glutathione (GSHm) as a novel mechanism of action resulting in redox disbalance and mitochondrial damage as mechanisms of pro-apoptotic effects of CDDO and CDDO-Me. Gene expression studies using cDNA arrays demonstrate that CDDO induces genes involved in the antioxidant response (AR) including phase II detoxifying enzymes (glutamate cysteine ligase, GSH transferase, etc.) and antioxidant enzymes (heme oxygenase 1, thioredoxin reductase). Cotreatment with the GSH precursor, n-acetyl cystein prevented apoptosis and loss of viability induced by CDDOs, whereas alkylation of intracellular thiols by diethylmaleate decreased the accumulation of a biotinylated derivative of CDDO, TP-301, in U937 leukemic cells suggesting that intracellular reduced thiols are functional targets of CDDO and its derivatives. The in vivo studies using liposomal CDDO-Me in a conditional leukemia model demonstrated significant reduction of leukemia burden as measured by bioluminescence imaging and prolongation of survival. Based on the ample pre-clinical evidence of anti-leukemia effects and on the favorable PK/toxicity profile of the parental compound, CDDO will enter Phase I clinical trials in hematologic malignancies in 3Q 2005 and CDDO-Me in 1Q 2006.
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Setiawan, A. M., A. A. Syafrianno, R. Rahmat, and Supari. "High-Resolution North Sulawesi Drought Hazzard Mapping Based on Consecutive Dry Days (CDD)." IOP Conference Series: Earth and Environmental Science 893, no. 1 (November 1, 2021): 012018. http://dx.doi.org/10.1088/1755-1315/893/1/012018.
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Abstract North Sulawesi is one of the Province in northern Indonesia with high spatial annual rainfall variations and influenced by global climate anomaly that can lead to extreme events and disaster occurrence, such as flood, landslide, drought, etc. The purpose of this study is to generate high-resolution meteorological hazard map based on long-term historical consecutive dry days (CDD) over the North Sulawesi region. CDD was calculated based on observed daily precipitation data from Indonesia Agency for Meteorology, Climatology, and Geophysics (BMKG) surface observation station network (CDDobs) and the daily-improved Climate Hazards group Infrared Precipitation with Stations (CHIRPS) version 2.0 (CDDCHIRPS) during 1981 – 2010 period. The Japanese 55-year Reanalysis (JRA-55) data obtained from iTacs (Interactive Tool for Analysis of the Climate System) with the same time scale period also used to explain physical – dynamical atmospheric properties related to drought hazard over this region. The Geostatistical approach using regression kriging method was applied as spatial interpolation technique to generate high resolution gridded (0.05° × 0.05°) drought hazard map. This method combines a regression of CDDobs as dependent variable (target variable) on CDDCHIRPS as predictors with kriging of the prediction residuals. The results show that most of the areas were categorized as medium drought hazard level with CDD values ranging from 80-100 days. Meanwhile, small islands around main Sulawesi island such as Sangihe and Karakelong island are dominated by low drought hazard levels with CDD values ranging from 50-60 days. The highest levels of drought hazard area are located in South Bolaang Mongondow Regency.
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Panwar, Kuldeep, Dinesh Prasad, Mayank Srivastava, and Zainab Haseeb. "New Current Mode Lossy Integrator Employing CDDITA." Circuits and Systems 09, no. 08 (2018): 117–23. http://dx.doi.org/10.4236/cs.2018.98012.
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Wang, Yongping, Weston W. Porter, Nanjoo Suh, Tadashi Honda, Gordon W. Gribble, Lisa M. Leesnitzer, Kelli D. Plunket, et al. "A Synthetic Triterpenoid, 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO), Is a Ligand for the Peroxisome Proliferator-Activated Receptor γ." Molecular Endocrinology 14, no. 10 (October 1, 2000): 1550–56. http://dx.doi.org/10.1210/mend.14.10.0545.
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Abstract A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor γ (PPARγ). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARγ, rosiglitazone. Binding studies of CDDO to PPARγ using a scintillation proximity assay give a Ki between 10−8 to 10−7m. In transactivation assays, CDDO is a partial agonist for PPARγ. The methyl ester of CDDO, CDDO-Me, binds to PPARγ with similar affinity, but is an antagonist. Like other PPARγ ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARγ, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARγ. Our results establish the triterpenoid CDDO as a member of a new class of PPARγ ligands.
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Ikeda, Takashi, Yukiko Nakata, Fumihiko Kimura, Ken Sato, Kenneth Anderson, Kazuo Motoyoshi, Michael Sporn, and Donald Kufe. "Induction of redox imbalance and apoptosis in multiple myeloma cells by the novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid." Molecular Cancer Therapeutics 3, no. 1 (January 1, 2004): 39–45. http://dx.doi.org/10.1158/1535-7163.39.3.1.
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Abstract The synthetic oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its chemical derivatives induce differentiation and apoptosis of human leukemia cells. The precise mechanisms responsible for the effects of CDDO, however, remain unclear. In the present study, we examined the effects of CDDO and its C-28 imidazolide ester (CDDO-Im) on apoptosis of multiple myeloma (MM) cells. The results show that both CDDO and CDDO-Im are potent inducers of MM cell apoptosis and that CDDO-Im is more active than CDDO. CDDO-Im treatment was associated with (a) depletion of glutathione, (b) increases in reactive oxygen species, (c) a reduction of the Fas-associated death domain (FADD)-like interleukin-1-converting enzyme (FLICE) inhibitory protein, (d) activation of caspase-8, and (e) a decrease of the mitochondrial transmembrane potential. The reducing agents, N-acetyl-l-cysteine, DTT, and catalase inhibited each of these CDDO-Im-induced proapoptotic signals. Inhibition of caspase-8 with z-IETD-fmk also abrogated CDDO-Im-induced decreases of the mitochondrial transmembrane potential and inhibited apoptosis. These results demonstrate that CDDO-Im disrupts intracellular redox balance and thereby activates the extrinsic caspase-8-dependent apoptotic pathway. We further show that CDDO-Im induces apoptosis of primary MM cells at submicromolar concentrations and that MM cells are more sensitive to this agent than normal bone marrow mononuclear cells. These results suggest that CDDO compounds have potential as new agents for the treatment of MM.
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Koh, Eun-Young, Keun-Sik Kim, Hee-Bin Park, Jong-Seok Kim, and Pyung-Hwan Kim. "Active Targeting of Versatile Nanocomplex Using the Novel Biomarker of Breast Cancer Stem Cells." International Journal of Molecular Sciences 24, no. 1 (December 30, 2022): 685. http://dx.doi.org/10.3390/ijms24010685.
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Breast cancer in women is one of the most common life-threatening malignancies. Despite of the development for the improved treatment, there are still many limitations to overcome. Among them, cancer stem cells (CSCs) are well known for tumor formation, development, cellular heterogeneity, and cancer recurrence. Therefore, to completely cure breast cancer, treatment of both cancer and CSC is required. To selectively target CSCs, we generated a liposome-based smart nano complex using CEACAM 6 (CD66c) antibody (Ab), a novel cell-surface biomarker of breast-derived CSCs (BCSCs) discovered in our previous research. Selective and increased cellular uptake was observed in BCSCs treated with CD66c Ab-conjugated rhodamine-labeled liposomes (CDRHOL) depending on the expression level of CD66c. CD66c Ab-conjugated doxorubicin (DOX)-loaded liposomes (CDDOXL) selectively showed increased cell killing effects in BCSCs with high CD66c expression levels. In an in vivo animal study, CDRHOL showed enhanced accumulation in xenografted BCSC tumors with low delivery into non-target organs. Moreover, mice treated with CDDOXL have assessed the decreased induction ability of immune response by low expression levels of pro-inflammatory cytokines and reduced liver toxicity by histopathological analysis. Finally, the improved antitumor effect of CDDOXL was evaluated in a metastatic BCSC mouse model via systemic administration. Collectively, our study is the first to demonstrate that a multi-functional nano complex using a novel surface biomarker of BCSC may be a more effective therapeutic agent for the treatment of cancer and CSCs.
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Kress, Christina L., Marina Konopleva, Maryla Krajewska, Vanesa Martinez-Garcia, Sophie Lefebvre, Marc L. Hyer, Teresa McQueen, Michael Andreeff, John C. Reed, and Juan Zapata. "Triterpenoids Display Single Agent Activity in a Mouse Model of CLL/SBL." Blood 108, no. 11 (November 16, 2006): 2530. http://dx.doi.org/10.1182/blood.v108.11.2530.2530.
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Abstract The synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) induces apoptosis of leukemia cells through a novel mechanism and has recently entered Phase I human clinical trials. We studied the effects of CDDO and its imidazolide derivative (CDDO-Im) on cultured human chronic lymphocytic leukemia (CLL) cells and on B cells from TRAF2DN/Bcl-2 transgenic mice, a new mouse model of CLL and small B cell lymphoma (SBL). Both triterpenoids efficiently induced death of malignant human and mouse B-cells ex vivo, although CDDO-Im was over 10-fold more potent than CDDO. Treating TRAF2DN/Bcl-2 mice that had developed leukemia with liposome-formulated CDDO or CDDO-Im resulted in significant reductions of B cells in blood, spleen and lung, with CDDO-Im more potent than CDDO, while treatment with empty liposomes had no impact on disease. Analysis of blood cells recovered from treated mice showed that CDDO-Im is a potent inducer of cell dead in vivo. Furthermore, CDDO-Im efficiently eradicated mouse CLL cells but had a lesser effect on the viability of normal B cells. These results demonstrate that triterpenoids CDDO and CDDO-Im reduce leukemia and lymphoma burden in vivo in a transgenic mouse model of CLL/SBL and suggest that CDDO-based synthetic triterpenoids should be tested for clinical activity in patients with CLL. Our results also provide evidence of the suitability of our mouse model of CLL/SBL as a preclinical platform for chemotherapeutic drug testing.
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Brookes, Paul, Andrew Tompkins, Kimberly Morse, Shannon Hilchey, Suhail Salim, Denise Ray, Richard Phipps, and Steven H. Bernstein. "The Triterpenoids 2-cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO) and Their Imidazole (CDDO-Im) and Dinitrile Derivatives (DI-CDDO) Elicit Apoptosis through a Novel Mitochondrial Pathway." Blood 106, no. 11 (November 16, 2005): 2426. http://dx.doi.org/10.1182/blood.v106.11.2426.2426.
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Abstract We have recently shown that B-cell non Hodgkin’s lymphoma express the transcription factor PPARγ and undergo apoptosis upon exposure to PPARγ ligands. The synthetic triterpenoid CDDO is a specific ligand for PPARγ, and CDDO and its derivatives, CDDO-Im and DI-CDDO, induce diffuse large cell lymphoma (DLCL) death (OCI Ly10 and OCI Ly19 cells), with a potency of DI-CDDO>CDDO-Im>CDDO, suggesting that such agents have therapeutic potential in lymphoma. The natural PPARγ ligand, 15d-PGJ2 (which also elicits DLCL death), has previously been shown to inhibit mitochondrial complex I, enhance mitochondrial reactive oxygen species (ROS) generation, and react with protein thiols. Given that CDDO is structurally similar to 15d-PGJ2 we hypothesized that CDDO-induced cell death may similarly be mediated via complex I inhibition, ROS generation, thiol oxidation, and opening of a large membrane pore complex in the mitochondrial membrane, termed the “permeability transition” (PT) pore. Studies on isolated rat liver mitochondria however showed that none of the CDDO-derivatives inhibited complex I activity or affected mitochondrial protein thiols. However, all three compounds did induce PT pore opening and mitochondrial swelling, with a concurrent loss of mitochondrial membrane potential, in a Ca2+ dependent manner (potency DI-CDDO>CDDO-Im>CDDO). This is consistent with a previously shown role for Ca2+ in CDDO-induced cell death. Interestingly, this mitochondrial swelling was not inhibited by the classical PT pore inhibitor cyclosporin A (CsA). This is supported by our findings that the induction of OCI-Ly19 cell death by CDDO was also not inhibited by CsA, or by another classical PT pore inhibitor, nortriptyline. These phenomena may be partially explained by invoking the “unregulated PT pore”. In addition to the classical PT pore, a non-CsA sensitive “unregulated PT pore” also exists, which is generated by the aggregation of misfolded mitochondrial membrane proteins that are induced by oxidants and thiol reactive agents. That exposure of mitochondria to CDDO results in the formation of “unregulated PT pores” is supported by our findings that the proteosome inhibitor PS341, potentiates CDDO-induced cell death, suggesting the involvement of a protein folding response. The temporal role of ROS in CDDO-induced cell death was also investigated, and it was found that the antioxidant N-acetyl-cysteine did not inhibit PT pore opening, but did inhibit cell death. This is consistent with our observation that ROS generation in isolated mitochondria was not immediately triggered by CDDO, but rather increased at delayed time points, placing it downstream of PT pore opening. This proposes the following novel model of a direct mitochondrial effect of CDDO and its derivatives: \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[CDDO{\rightarrow}\ mitochondrial\ protein\ misfolding\ {\rightarrow}\ unregulated\ PT\ pore\ formation\ {\rightarrow}\ ROS\ {\rightarrow}\ cell\ death\] \end{document} In summary: CDDO and its derivatives have direct effects on mitochondria, and represent novel therapeutic approaches for the treatment of patients with DLCL; and combinations of CDDO and its derivatives with proteosome inhibitors represent a rational combination to test in the context of clinical trials.
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Elsawa, Sherine F., Anne J. Novak, Marina Konopleva, Michael Andreeff, Thomas E. Witzig, and Stephen M. Ansell. "Preferential Inhibition of Malignant Cell Growth by CDDO in Waldenström Macroglobulinemia." Blood 108, no. 11 (November 16, 2006): 2528. http://dx.doi.org/10.1182/blood.v108.11.2528.2528.
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Waldenström macroglobulinemia (WM) is a B cell disorder with a highly variable clinical outcome, where some patients remain asymptomatic, while others have significant symptoms and require therapeutic intervention. Clinical symptoms include infiltration of lymphoplasmacytic cells into the bone marrow, production of a monoclonal IgM protein, anemia, lymphadenopathy, and serum hyperviscosity. Despite the introduction of multiple chemotherapeutic regimens over the past several decades, WM remains an incurable disease. 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its methyl ester derivative (CDDO-Me) and imidazolide derivative (CDDO-Im) are synthetic triterpenoids derived from oleanolic acid. These compounds have been shown to induce apoptosis of several tumor cell types including breast cancer, lung cancer, ovarian cancer, melanoma, osteosarcoma, leukemia, and multiple myeloma cells. The goal of this study was to evaluate the potential role of synthetic triterpenoids in WM. Preliminary studies on malignant B cells indicated that CDDO-Im induced the greatest amount of cell death and we therefore used this derivative of CDDO for our studies. CD19+ CD138+ cells from bone marrow biopsy specimens obtained from WM patients were isolated by positive selection and were treated with varying concentrations of CDDO-Im (62.5 nM to 750 nM ) and cell viability was determined after 24 hours (n=3). Compared to the nil control 47% of the malignant cells remained viable at a CDDO-Im concentration of 62.5 nM and only 11% remained viable at 125 nM CDDO-Im. To determine if CDDO-Im had specific toxic effects on non-malignant cells, we cultured CD19- CD138- cells from WM patient bone marrows with CDDO-Im and found that non-malignant cells were less sensitive to the drug, 80% being viable at 62.5 nM and 65% being viable at 125 nM. Similarly, we found that normal peripheral blood B cells and CD19+ CD138+ bone marrow B cells from healthy donors were less sensitive to CDDO-Im. Compared to the nil control 93% of the CD19+ CD138+ bone marrow B cells and 70% of the peripheral blood B cells remained viable at a CDDO-Im concentration of 62.5 nM and 95% and 68% remained viable at 125 nM CDDO-Im respectively. We next examined the effect of CDDO-Im on WM cell proliferation and found that CDDO-Im inhibited cell proliferation in a dose-dependent manner. Similar to the viability assays, there was a differential effect of CDDO-Im on malignant and non-malignant cells. Compared to the nil control, at 125 nM, there was a complete inhibition of malignant cell growth, while approximately 40% of the non-malignant cells remained proliferative. To determine the mechanism of cell death, CD19+ CD138+ cells were cultured in the presence or absence of various doses of CDDO-Im for 6 hours and cell lysates were examined for cleavage of PARP. There was evidence of PARP cleavage in a dose-dependent manner, suggesting that CDDO-Im induced malignant cell death occurs through a caspase-dependent mechanism. In summary, the synthetic triterpenoid CDDO-Im decreased the viability of WM B cells in a dose-dependent manner, and CDDO-Im had a greater effect on the viability of the malignant cells compared to non-malignant cells from the same WM patients. CDDO-Im also inhibited malignant cell growth in a dose-dependent manner and the mechanism of CDDO-Im mediated cell death appears to be a caspase-mediated event. Overall, our data indicate that CDDO-Im may have potential efficacy in WM patients.
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Konopleva, Marina, Twee Tsao, Peter Ruvolo, Irina Stiouf, Zeev Estrov, Clinton E. Leysath, Shourong Zhao, et al. "Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia." Blood 99, no. 1 (January 1, 2002): 326–35. http://dx.doi.org/10.1182/blood.v99.1.326.
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It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1–overexpressing, p53null HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34+ progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1– and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
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Kim, Ji-Eun, Hana Park, and Tae-Cheon Kang. "CDDO-Me Distinctly Regulates Regional Specific Astroglial Responses to Status Epilepticus via ERK1/2-Nrf2, PTEN-PI3K-AKT and NFκB Signaling Pathways." Antioxidants 9, no. 10 (October 21, 2020): 1026. http://dx.doi.org/10.3390/antiox9101026.
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2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid. CDDO-Me shows anti-inflammatory and neuroprotective effects. Furthermore, CDDO-Me has antioxidant properties, since it activates nuclear factor-erythroid 2-related factor 2 (Nrf2), which is a key player of redox homeostasis. In the present study, we evaluated whether CDDO-Me affects astroglial responses to status epilepticus (SE, a prolonged seizure activity) in the rat hippocampus in order to understand the underlying mechanisms of reactive astrogliosis and astroglial apoptosis. Under physiological conditions, CDDO-Me increased Nrf2 expression in the hippocampus without altering activities (phosphorylations) of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphatidylinositol-3-kinase (PI3K), and AKT. CDDO-Me did not affect seizure activity in response to pilocarpine. However, CDDO-Me ameliorated reduced astroglial Nrf2 expression in the CA1 region and the molecular layer of the dentate gyrus (ML), and attenuated reactive astrogliosis and ML astroglial apoptosis following SE. In CA1 astrocytes, CDDO-Me inhibited the PI3K/AKT pathway by activating PTEN. In contrast, CDDO-ME resulted in extracellular signal-related kinases 1/2 (ERK1/2)-mediated Nrf2 upregulation in ML astrocytes. Furthermore, CDDO-Me decreased nuclear factor-κB (NFκB) phosphorylation in both CA1 and ML astrocytes. Therefore, our findings suggest that CDDO-Me may attenuate SE-induced reactive astrogliosis and astroglial apoptosis via regulation of ERK1/2-Nrf2, PTEN-PI3K-AKT, and NFκB signaling pathways.
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Chauhan, Dharminder, Guilan Li, Klaus Podar, Teru Hideshima, Reshma Shringarpure, Laurence Catley, Constantine Mitsiades, et al. "The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti–multiple myeloma (MM) activity and overcome bortezomib resistance." Blood 103, no. 8 (April 15, 2004): 3158–66. http://dx.doi.org/10.1182/blood-2003-08-2873.
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Abstract The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO) induces apoptosis in leukemic cells. Here we show that CDDO and its new derivative CDDO-imidazolide (CDDO-Im) trigger apoptosis in multiple myeloma (MM) cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40), and dexamethasone (MM.1R, U266, RPMI 8226) without affecting the viability of normal cells. CDDO-IM also triggers apoptosis in bone marrow stromal cells (BMSCs) and decreases interleukin-6 (IL-6) secretion induced by MM cell adhesion to BMSCs. Moreover, CDDO-Im–induced apoptosis in MM cells is not blocked by IL-6 or insulin growth factor-1 (IGF-1). Importantly, CDDO-Im and bortezomib/proteasome inhibitor PS-341 trigger synergistic apoptosis in MM cells associated with loss of mitochondrial membrane potential, superoxide generation, release of mitochondrial proteinscytochrome c/second mitochondria-derived activator of caspases (cyctochrome c/Smac), and activation of caspase-8, -9, and -3. Conversely, the pancaspase inhibitor Z-VAD-fmk abrogates the CDDO-Im + bortezomib–induced apoptosis. Low doses of CDDO-Im and bortezomib overcome the cytoprotective effects of antiapoptotic proteins Bcl2 and heat shock protein-27 (Hsp27) as well as nuclear factor–kappa B (NF-κB)–mediated growth/survival and drug resistance. Finally, combining CDDO-Im and bortezomib induces apoptosis even in bortezomib-resistant MM patient cells. Together, these findings provide the framework for clinical evaluation of CDDO-Im, either alone or in combination with bortezomib, to overcome drug resistance and improve patient outcome in MM. (Blood. 2004;103: 3158-3166)
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Ray, Denise, Kimberly Morse, Shannon Hilchey, Tatiana Garcia, Raymond Felgar, Sanjay Maggirwar, Richard Phipps, and Steven H. Bernstein. "The Novel Triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO) Induces Apoptosis of Human Diffuse Large B-Cell Lymphoma Cells (DLCL) through a Peroxisome Proliferator-Activated Receptor γ (PPARγ) Independent Pathway Which Is Enhanced by NFκB Inhibition." Blood 106, no. 11 (November 16, 2005): 2425. http://dx.doi.org/10.1182/blood.v106.11.2425.2425.
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Abstract Ligands for the transcription factor PPARγ are emerging as a new class of anti-tumor agents. Herein we report that the synthetic triterpenoid CDDO, a PPARγ ligand that induces PPARγ transcriptional activity in human DLCL OCI-Ly-19 cells, also induces cell death in human DLCL of both germinal center (OCI-Ly19) and activated B-cell phenotype (OCI-Ly10), cells which express the PPARγ protein. This effect of CDDO appears to be independent of PPARγ stimulated pathways since the functional antagonist of PPARγ, GW9662, which completely inhibits CDDO induced PPARγ transcriptional activity was unable to prevent CDDO induced cell death. Similar findings were seen using the additional PPARγ antagonists T0070907 and BADGE. CDDO induces cell death by inhibiting cell proliferation and inducing apoptosis as shown by Annexin-V and propidium iodide staining. As we have previously shown that PPARγ ligands inhibit NF-κB activity in B lymphocytes (J. Immunol2005; 174(7): 4060–9), we next examined the effect of CDDO on NF-κB in DLCL cells. Surprisingly, exposure of Ly19 cells to CDDO resulted in a dose-, and time-dependent increase in the activity of both the p50 and p65 subunits of NF-κB as determined by ELISA, by direct visualization of the nuclear translocation of p65 using indirect immunofluorescence assays, and by EMSA. The nuclear translocation of both the p50 and p65 NF-κB subunits was also confirmed by performing immunoblot analyses using nuclear fractions of CDDO-treated Ly19 cells. NF-κB activation was also observed in Ly10 cells exposed to CDDO. Follow-up experiments revealed that the activation of NF-κB in Ly19 cells by CDDO was due to proteolysis of inhibitory IκBα molecules. To determine whether the CDDO-induced NF-κB activation was a pro- survival mechanism, Ly19 and Ly10 cells were pre-treated with the NF-κB inhibitors SN50, helenalin or BAY 11-7082 and then exposed to CDDO for 24 hrs. In all cases, the NF-κB inhibitors significantly enhanced CDDO induced cell death suggesting that NF-κB activation is an anti-apoptotic mechanism elicited to protect the cell against CDDO cytotoxicity. Collectively, these studies suggest that; (a) CDDO (which will shortly be entering clinical trials for patients with acute myeloid leukemia) as a single agent may have significant clinical activity in patients with DLCL and; (b) the combination of CDDO with pharmacological inhibitors of NF-κB would be a rationale combination of novel agents to test in the context of clinical trials for patients with DLCL.
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Welniak, Lisbeth A., Salif Harouna, David Prosser, Erik Ames, Colin Meyer, and William J. Murphy. "The Antioxidant Inflammation Modulator, CDDO-Me Promotes Myelopoiesis in Mice." Blood 112, no. 11 (November 16, 2008): 2335. http://dx.doi.org/10.1182/blood.v112.11.2335.2335.
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Abstract CDDO-me (methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate)is a novel antioxidant inflammation modulator that has been shown to suppress tumor-induced inflammatory processes through suppression of NF-kB and STAT3 and induce apoptosis and differentiation of human leukemic and solid tumor cells.. It has also been shown to be more potent than the parent compound, CDDO against leukemia cells. We have previously shown that administration of CDDO, when given peri-transplant, can inhibit the development of acute murine GVHD and induces cell death in proliferating but not resting lymphocytes in a mixed lymphocyte culture. We therefore next sought to determine the effect of CDDO-me administration on normal hematopoiesis in naive and myelosuppressed mice. Administration of CDDO-me (120 ug/dose BID for 7 days) to C56BL/6 mice did not significantly affect the number of T and B cells in the spleen. Unexpectedly, CDDO-me administration resulted in a significant expansion of myeloid cells in the bone marrow and spleen, predominately CD11b+Ly6CintGR1hi neutrophils. To determine if CDDO-me acted primarily on terminal stages of differentiation or at early phases on development in hematopoiesis, we performed clonogeneic assays for myeloid (CFU-GM), erythroid (BFU-E) and primitive, high proliferative potential (CFU-HPP) precursors and compared treatment with CDDO-me with rhG-CSF administration, a cytokine known to promote expansion and mobilization of hematopoietic precursors from the bone marrow. Administration of CDDO-me resulted in significant expansion of myeloid and erythroid progenitors in the spleen and blood although not to the same extent as that observed in mice receiving 2.5 ug/dose BID rhG-CSF. Unlike the mobilization seen with rhG-CSF where hematopoietic precursors were decreased in the bone marrow, CDDO-me significantly increased the number of myeloid, erythroid and CFU-HPPs in the marrow. Administration of CDDO-me prior to myelosuppression with sublethal total body irradiation also resulted in significant increase of spleen cellularity after 8 days recovery due to significant expansion of myeloid cells as well as increases in B cells. However, CDDO-me did not significantly impact hematopoietic recovery compared to vehicle control treated animals when CDDO-me was given to mice following sublethal total body irradiation. These results suggest that CDDO-me can expand early hematopoietic precursors in mice, resulting in radioprotection. Stimulation of myelopoiesis in vivo by CDDO-me can be accounted for, in part, by a significant increase in circulating G-CSF levels in treated animals. However, the retention of hematopoietic precursors in the bone marrow of mice that received CDDO-me but not rhG-CSF suggest additional mechanisms are involved. These results demonstrate that CDDO-me significantly affects normal hematopoietic cells including precursor populations in vivo and can promote granulopoiesis predominately in non-irradiated mice.
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Zapata, Juan M., Christina L. Kress, Marina Konopleva, Maryla Krajewska, Mark Hyer, Teresa McQueen, and Michael Andreeff. "CDDO and CDDO-Im Reduce Tumor Burden in a Transgenic Mouse Model of CLL." Blood 104, no. 11 (November 16, 2004): 3477. http://dx.doi.org/10.1182/blood.v104.11.3477.3477.
Full textAbstract:
Abstract Transgenic mice over-expressing in B lymphocytes both Bcl-2 and a TRAF2 mutant lacking the N-terminal RING and zinc finger domains (TRAF2DN), which mimics TRAF1, develop small B cell lymphoma and leukemia that have remarkably similar characteristics to human chronic lymphocytic leukemia (CLL). TRAF2DN/Bcl-2 mice develop over time leukemia, severe splenomegaly, and lymphadenopathy, which are associated with monoclonal and oligoclonal B cell neoplasms. The lifespan of TRAF2DN/Bcl-2 mice is markedly reduced compared to Bcl-2 and TRAF2DN single transgenics or wild-type littermates. The expanded B cell population in the blood of leukemic TRAF2DN/Bcl-2 double transgenic mice is primarily comprised of small-medium size, non-cycling B220M/IgMH/IgDL/CD21L/CD23−/CD11b+/CD5+ cells that were Bcl-6 negative, consistent with a B-1 phenotype, closely resembling their human CLL counterparts. Indeed, these B cells showed comparable proliferation rates to normal B-cells, but exhibited markedly increased survival and were resistant to apoptosis induced by chemotherapeutic agents and glucocorticoids. We studied the effects of synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and its imidazolide derivative (CDDO-Im) on cultured B-cells from the TRAF2DN/Bcl-2 transgenic mice. Both CDDO and CDDO-Im efficiently induced apoptosis of these cells in vitro, although CDDO-Im was approximately 10-times more potent than CDDO (LD50: 0.35μM CDDO-Im vs 3.8 μM CDDO). To study the effect of CDDO and CDDO-Im in vivo, groups of TRAF2DN/Bcl-2 mice that had developed leukemia were injected i.v. with liposomes alone or liposomes containing either CDDO or CDDO-Im, at a dose of 20 mg/kg/day. Each mouse received a total of nine injections administered over a period of 22 days. The concentration of B cells in the blood of these mice was monitored daily after each injection, using a mini-FACS (Guava Technologies, Inc.). CDDO-treated mice showed a steady reduction in the number of leukemic cells in blood during the treatment and this tendency was maintained 10 days after the last treatment. In contrast, CDDO-Im treated mice showed a striking increase in the concentration of B cells in blood (B220+ events) immediately after the first inoculation. One mouse of this group died after the first injection, and 2 more mice died after 5 injections. Only 2 mice treated with CDDO-Im survived the full treatment, showing a striking reduction of leukemic cells in blood by the end of the treatment. Administration of empty liposomes had no inhibitory effect on the leukemia, and mice in this control group had massive splenomegaly (1431±323 mg; n=3) and severe disseminated lymphadenopathy. In contrast, CDDO-treated mice had less severe splenomegaly (938±234; n=4) but still had severe lymphadenopathy. CDDO-Im treated mice showed a dramatic reduction in the spleen size that was evident also in those mice that died after 5 injections (474±185 mg; n=4) and had no signs of lymphadenopathy. Although preliminary, these results indicate that in vivo administration of CDDO and CDDO-Im reduced the tumor burden in a transgenic model of CLL, and illustrate the potential of triterpenoids as single agents for the treatment of CLL.
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Chang, Chih-Hui, Hung-Pei Tsai, Shih-Hsun Kuo, Joon-Khim Loh, Chien-Ju Lin, Chih-Lung Lin, and Aij-Lie Kwan. "Synthetic Triterpenoid CDDO-Me Inhibits Proliferation, Migration, and Invasion in GBM8401 and GBM8901." International Surgery 104, no. 3-4 (March 1, 2020): 90–98. http://dx.doi.org/10.9738/intsurg-d-20-00005.1.
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Objectives: We determined the anticancer potency of CDDO-Me in glioblastoma cell lines and the underlying mechanisms in vitro. Summary: CDDO-Me is a synthetic triterpenoid with more potent anticancer and cancer preventive actions compared with the original triterpenoid CDDO. Methods: Two glioblastoma cell lines, GBM8401 and GBM8901, were utilized to test the effect of CDDO-Me on cell viability, cell migration, and cell invasion using the MTT, wound healing, and transwell migration assays, respectively. Additionally, Western blotting was used to determine the protein expression levels of N-cadherin, cyclin D1, and vascular endothelial growth factor. Results: At nanomolar concentrations, CDDO-Me inhibited proliferation, migration, and invasion in both cell lines. In addition, CDDO-Me exhibited a dose-dependent downregulation in the protein levels of N-cadherin, cyclin D1, and vascular endothelial growth factor in GBM8401 and GBM8901 cells. Conclusions: CDDO-Me exhibited anticancer effects at low nanomolar concentrations and should be considered as a potential chemotherapeutic agent for glioblastoma.
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Koschmieder, Steffen, Francesco D'Alò, Hanna Radomska, Christine Schöneich, Ji Suk Chang, Marina Konopleva, Susumu Kobayashi, et al. "CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer–binding protein alpha." Blood 110, no. 10 (November 15, 2007): 3695–705. http://dx.doi.org/10.1182/blood-2006-11-058941.
Full textAbstract:
Abstract 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of tumor cells in vitro and in vivo. Here we assessed the effects of CDDO on CCAAT enhancer–binding protein alpha (CEBPA), a transcription factor critical for granulocytic differentiation. In HL60 acute myeloid leukemia (AML) cells, CDDO (0.01 to 2 μM) induces apoptosis in a dose-dependent manner. Conversely, subapoptotic doses of CDDO promote phagocytic activity and granulocytic-monocytic differentiation of HL60 cells through increased de novo synthesis of p42 CEBPA protein. CEBPA translational up-regulation is required for CDDO-induced granulocytic differentiation and depends on the integrity of the CEBPA upstream open reading frame (uORF). Moreover, CDDO increases the ratio of transcriptionally active p42 and the inactive p30 CEBPA isoform, which, in turn, leads to transcriptional activation of CEBPA-regulated genes (eg, GSCFR) and is associated with dephosphorylation of eIF2α and phosphorylation of eIF4E. In concordance with these results, CDDO induces a CEBPA ratio change and differentiation of primary blasts from patients with acute myeloid leukemia (AML). Because AML is characterized by arrested differentiation, our data suggest the inclusion of CDDO in the therapy of AML characterized by dysfunctional CEBPA expression.
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Borella, Rebecca, Luca Forti, Lara Gibellini, Anna De Gaetano, Sara De Biasi, Milena Nasi, Andrea Cossarizza, and Marcello Pinti. "Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids." Molecules 24, no. 22 (November 13, 2019): 4097. http://dx.doi.org/10.3390/molecules24224097.
Full textAbstract:
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me.
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Konopleva, Marina, Peter Ruvolo, Rooha Contractor, Svitlana Kurinna, Yue-Xi Shi, Teresa McQueen, Michele Milella, and Michael Andreeff. "Triterpenoid Methyl-CDDO Is a Potent Inducer of Apoptosis in CD34+ AML Progenitor Cells Via Activation of SAPK Pathways and Inhibition of MAPK Cascades." Blood 104, no. 11 (November 16, 2004): 2533. http://dx.doi.org/10.1182/blood.v104.11.2533.2533.
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Abstract Outcome results in AML are a continued challenge for the development of novel therapeutic strategies. C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid, CDDO-Me, a novel triterpenoid, induces apoptosis in myeloid and lymphoid leukemic cell lines and in primary AML samples in sub-micromolar concentrations. We reported previously that CDDO-Me inhibits the activation of ERK1/2, blocks Bcl-2 phosphorylation, and promoted apoptosis in AML-derived U937 cells (Blood 2002, 99(1):326–35). Here, we examined the effects of CDDO-Me on CD34+ AML progenitor cells in vitro. Exposure to 1μM CDDO-Me induced apoptosis in all but one AML sample (46±4% annexin(+) CD34+ cells, n=20). To assess the anti-leukemia activity of CDDO-Me in vivo, scid mice intravenously injected with U937 cells were treated with liposomally-delivered CDDO-Me (20mg/kg/day IV every other day, starting at day 7, for a total of 9 injections). While CDDO-Me was not toxic to the mice, pathological and flow cytometry analysis revealed reduced (55–86%) leukemia burden in the bone marrow, liver, and spleen of mice. Since we had shown that CDDO-Me inhibits phosphorylation of pERK in U937 cells, a further goal of this study was to assess the role of ERK in CDDO-Me-induced cell death in primary AML samples. ERK was expressed and phosphorylated in all (n=15) patients’ samples studied. CDDO-Me inhibited ERK phosphorylation in 9 of 15 patient samples and promoted apoptosis. However, CDDO-Me still induced apoptosis in 5/6 samples that displayed no significant changes in pERK levels in response to the drug. This finding suggests that ERK is not the sole target of the compound. The stress-activated protein kinases JNK and p38 are related to ERK but in general activate pathways that are opposed to ERK. By Western blot analysis, CDDO-Me induced early (30 min) phosphorylation of JNK and p38, which preceded induction of cell death. Pre-treatment of U937 cells with JNK and p38 inhibitors SP600125 and SB203580 partially abrogated induction of apoptosis, while MEK inhibitor PD-98059 significantly enhanced cytotoxicity. CDDO-Me induced p38 phosphorylation in 5 of 6 primary AML samples tested. Collectively, these finding indicate that CDDO-Me markedly shifts signaling toward the JNK and p38 MAPK stress-related pathways and away from the cytoprotective MAPK cascade. In summary, the triterpenoid CDDO-Me is a potent inducer of apoptosis in primary AML including CD34+ AML progenitor cells. Induction of apoptosis is in part mediated via inhibition of ERK signaling combined with JNK/p38 activation. These studies in primary AML samples and the anti-leukemia activity of the compound in vivo suggest potential utility of CDDO-Me for the treatment of AML patients.
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Kim, Min-Ju, Hana Park, Seo-Hyeon Choi, Min-Jeong Kong, Ji-Eun Kim, and Tae-Cheon Kang. "CDDO-Me Attenuates Vasogenic Edema and Astroglial Death by Regulating NF-κB p65 Phosphorylations and Nrf2 Expression Following Status Epilepticus." International Journal of Molecular Sciences 20, no. 19 (September 30, 2019): 4862. http://dx.doi.org/10.3390/ijms20194862.
Full textAbstract:
2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that has anti-inflammatory, antioxidant, and neuroprotective activities. In the present study, we evaluate the effects of CDDO-Me on serum extravasation and astroglial death in the rat piriform cortex (PC) induced by status epilepticus (a prolonged seizure activity, SE) in order to propose an underlying pharmacological mechanism of CDDO-Me and its availability for treatment of vasogenic edema. CDDO-Me effectively mitigated serum extravasation and a massive astroglial loss in the PC following SE. CDDO-Me abrogated tumor necrosis factor-α (TNF-α) synthesis in activated microglia by inhibiting nuclear factor-κB (NF-κB) p65 serine 276 phosphorylation. CDDO-Me also abolished NF-κB threonine 435 phosphorylation in endothelial cells and TNF-α-mediated-phosphatidylinositol-3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling cascades, which trigger vasogenic edema following SE. Furthermore, CDDO-Me increased astroglial viability via the up-regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression. Therefore, our findings suggest that CDDO-Me may ameliorate SE-induced vasogenic edema formation by regulating NF-κB p65 phosphorylations in microglia as well as endothelial cells and enhancing Nrf2 expression in astrocytes, respectively.
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Pioli, Patricia Ann, Michael S. Ball, Rajan Bhandari, Gretel Maria Torres Santiesteban, Viktor Martyanov, Mohamed Eltanbouly, Michael L. Whitfield, and Karen Liby. "Redirecting Immune Activation in the Tumor Microenvironment of Estrogen Receptor Negative Breast Cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.37. http://dx.doi.org/10.4049/jimmunol.204.supp.242.37.
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Abstract The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immune suppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from tumor-promoting to tumor-inhibiting in vitro. We show now for the first time that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of CD4+ T cells were reduced, while the proportion of CD8+ T cells was significantly increased in tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of tumor CD4+Foxp3+ regulatory T cells. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.
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Tsai, Tai-Hsin, Cheng-Yu Tsai, Sin-Hua Moi, Chieh-Hsin Wu, Kuan-Ting Lee, Yi-Chiang Hsu, and Yu-Feng Su. "A Novel Synthetic Oleanolic Acid Derivative Inhibits Glioma Cell Proliferation by Regulating Cell Cycle G2/M Arrest." Pharmaceuticals 16, no. 5 (April 24, 2023): 642. http://dx.doi.org/10.3390/ph16050642.
Full textAbstract:
2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid-9,11-dihydro-trifluoroethyl amide (CDDO-dhTFEA) has antioxidant and anti-inflammatory activities; however, whether CDDO-dhTFEA has anticancer effects is unclear. The objective of this research was to investigate the possibility of CDDO-dhTFEA as a potential cancer-fighting treatment in glioblastoma cells. Our experiments were performed on U87MG and GBM8401 cells, and we found that CDDO-dhTFEA was effective in reducing cell proliferation in both cell lines, in a manner that was dependent on both time and concentration. Additionally, we observed that CDDO-dhTFEA had a significant impact on the regulation of cell proliferation, which was evident in the increase in DNA synthesis that was observed in both cell types. CDDO-dhTFEA induced G2/M cell cycle arrest and mitotic delay, which may be associated with the inhibition of proliferation. Treatment with CDDO-dhTFEA led to cell cycle G2/M arrest and inhibited proliferation of U87MG and GBM8401 cells by regulating G2/M cell cycle proteins and gene expression in GBM cells in vitro.
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Koschmieder, Steffen, Francesco D′Alo′, Hanna Radomska, Susumu Kobayashi, Elena Levantini, Nanjoo Suh, Michael B. Sporn, et al. "CDDO Increases Translation of CCAAT Enhancer Binding Protein alpha To Induce Granulocytic Differentiation." Blood 106, no. 11 (November 16, 2005): 2458. http://dx.doi.org/10.1182/blood.v106.11.2458.2458.
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Abstract The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel antineoplastic drug which induces apoptosis of a wide variety of tumor cells in vitro and in vivo and leads to granulocytic differentiation of hematopoietic progenitor cells. We studied the effect of CDDO on CCAAT enhancer binding protein alpha (CEBPA), a transcription factor which is critical for granulocytic differentiation. In HL60 myeloblastic cells, CDDO (0.01 to 2 uM) dose-dependently decreased the number of cells in culture and increased the fraction of apoptotic cells. However, at doses which did not induce apoptosis, CDDO increased the number of granulocytic cells, as assessed by morphology, NBT assay, and FACS, and Northern blotting showed an increase of GCSFR and a decrease of c-myc mRNA. Phagocytosis of FITC-labeled E. coli bacteria by these cells was enhanced by CDDO. While CEBPA mRNA was decreased, CEBPA protein was significantly increased within 24 hours of treatment, and this was not abrogated by preincubation with the caspase inhibitor Z-DEVD-fmk, again suggesting that these effects were independent of apoptosis. CDDO increased the ratio of the transcriptionally active isoform p42 and the inactive p30 isoform 3-fold, and gel shift assays showed enhanced DNA binding to a GCSFR promoter probe. Since eukaryotic translation initiation factors (eIF) have been described to alter the CEBPA protein isoform ratio, we studied the effects of CDDO on eiF2 alpha and eiF4E activity. CDDO increased the phosphorylation of eIF4E and decreased the phosphorylation of eIF2 alpha within 5 hours of treatment, and this was associated with an increase of the p42/p30 CEBPA ratio. In the presence of the translation inhibitor cycloheximide, CEBPA protein levels decreased after 2 hours, suggesting that CDDO did not stabilize CEBPA and that de novo protein synthesis was required for the observed effects. The effect of CDDO on the p42/p30 ratio was mimicked by 2-AP, which inhibits eIF2 alpha phosphorylation, but was independent of PPARgamma and TGFß pathways, as demonstrated by preincubation with GW9662, or TGFß1, respectively. In primary blasts from patients with acute myeloid leukemia (AML), the p42/p30 ratio of CEBPA was enhanced by CDDO treatment. In conclusion, CDDO leads to granulocytic differentiation and translational induction of CEBPA protein. Since CEBPA function is impaired in many patients with AML, CDDO may provide a novel treatment approach for these patients.
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Murphy, William J., Olga Frolova, Marina Konopleva, Michael Andreeff, Weihong Ma, Danice Wilkins, Lisbeth A. Welniak, and Kai Sun. "Immunomodulatory Effects of the Triterpenoid CDDO after Allogeneic Bone Marrow Transplantation in Mice: Reduction of Acute Graft-Versus-Host Disease Lethality." Blood 106, no. 11 (November 16, 2005): 1316. http://dx.doi.org/10.1182/blood.v106.11.1316.1316.
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Abstract The use of hematopoietic stem cell transplantation (HSCT) in cancer treatment is seriously hampered by the occurrence of graft-versus-host disease (GVHD) and cancer relapse. During acute GVHD, inflammatory cytokines play a pivotal role in the amplification of GVHD. Therefore, assessment of agents with known anti-neoplastic activity that also reduce cytokine production may be useful in both the prevention of GVHD and cancer relapse. The synthetic triterpenoid, CDDO (2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid) is multifunctional molecule which has shown potent anti-cancer activities both in vitro and in vivo through the induction of apoptosis. We first examined the effects of CDDO on both human and murine T cell mitogen responses in vitro. CDDO significantly inhibited mitogen responsiveness of both human and murine T cells in vitro with evidence of cell cycle arrest of the human T cells. We then proceeded to examine the effects of CDDO on acute GVHD induction and progression. In these studies, lethally irradiated C57BL/6 mice received 10 million bone marrow cells (BMC) and 40 million spleen cells from fully MHC-mismatched BALB/c donors. All of the control mice succumbed rapidly due to acute GVHD. In contrast, the mice that received CDDO (120 ug/BID) given from days 0-3 following BMT exhibited significant improvement in survival (P < 0.001). Body weights from the treated mice also were significantly increased compared to untreated controls. We found that the timing of CDDO administration was a critical factor for protection from GVHD as protection only occurred when CDDO was administered early after BMT. Importantly, donor myeloid reconstitution was not adversely affected by CDDO treatment as determined by peripheral blood cell count and donor chimerism assessment on day +14 post-transplant. No adverse toxicities or effects on reconstitution were observed in the mice receiving BMC alone with CDDO being administered continuously. Given the reported direct anti-tumor effects of CDDO, it will be of particular interest in examining the effects of CDDO and allogeneic BMT in tumor-bearing recipients. Our findings suggest that CDDO can enhance the efficacy of allogeneic BMT by decreasing acute GVHD in mice.
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Kurosaki, Yoshifumi, Akemi Imoto, Fumitaka Kawakami, Motoshi Ouchi, Asuka Morita, Masanori Yokoba, Tsuneo Takenaka, et al. "In vitro study on effect of bardoxolone methyl on cisplatin-induced cellular senescence in human proximal tubular cells." Molecular and Cellular Biochemistry 477, no. 3 (January 1, 2022): 689–99. http://dx.doi.org/10.1007/s11010-021-04295-y.
Full textAbstract:
AbstractBardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 μmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1, NQO1, GPX1, and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.
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Samudio, Ismael, Marina Konopleva, Numsen Hail, Yue-Xi Shi, Teresa McQueen, Timothy Hsu, Randall Evans, et al. "2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione to Induce Apoptosis in Pancreatic Cancer." Journal of Biological Chemistry 280, no. 43 (August 23, 2005): 36273–82. http://dx.doi.org/10.1074/jbc.m507518200.
Full textAbstract:
Surgical resection is the only curative strategy for pancreatic cancer (PC). Unfortunately, >80% of pancreatic cancer patients bear inoperable, locally advanced, chemoresistant tumors demonstrating the urgent need for development of novel therapeutic approaches to treat this disease. Here we report that the synthetic triterpenoid 2-cyano-3,12 dioxooleana-1,9 dien-28-imidazolide (CDDO-Im) antagonizes PC cell growth by inducing apoptosis at submicromolar concentrations. Notably, we demonstrate for the first time that the cytotoxicity of CDDO-Im is accompanied by the rapid and selective depletion of mitochondrial glutathione that results in accumulation of reactive oxygen species, oxidation of the cellular glutathione pool, loss of mitochondrial membrane potential, and phosphatidylserine externalization. The parent compound CDDO as well as the methyl ester of CDDO also depleted mitochondrial glutathione, demonstrating that this effect is mediated by the triterpenoid nucleus of these agents. Cotreatment with sulfhydryl nucleophiles completely prevented apoptosis and loss of viability induced by CDDO-Im, whereas alkylation of intracellular thiols by diethylmaleate or cotreatment with dithiothreitol decreased the accumulation of a biotinylated derivative of CDDO, TP-301, in PC cells, suggesting that intracellular reduced thiols are functional targets of the electrophilic triterpenoid nucleus of CDDO and its derivatives. In conclusion, our report is the first to identify mitochondrial glutathione as a target of CDDO and its derivatives and demonstrates that depletion of this antioxidant in the mitochondria is an effective strategy to induce cell death in PC cells. These results suggest that CDDO and its derivatives may offer a clinical benefit for the treatment of PC.
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Huang, Youqun, Mulin Ye, Chunlin Wang, Zhenfen Wang, and Weiping Zhou. "Protective effect of CDDO-imidazolide against intestinal ischemia/reperfusion injury in mice." European Journal of Inflammation 16 (January 2018): 205873921880268. http://dx.doi.org/10.1177/2058739218802681.
Full textAbstract:
Intestinal ischemia/reperfusion (I/R) is life-threatening and challenging in clinical practice. CDDO-imidazolide (CDDO-Im) is therapeutic in alleviating I/R injury. Nevertheless, there is a lack of investigation on the effects of CDDO-Im on intestinal I/R. Mice were randomly divided into four groups: (a) the sham group, (b) the CDDO-Im group, (c) the I/R group, and (d) the I/R + CDDO-Im group. Intestinal I/R was performed by clamping arteria mesenteric anterior for 45 min, followed by 24 h reperfusion. In addition, Kaplan–Meier method and the log-rank test were used to compare the survival rates among groups by observing for 24 h. Intestinal I/R in model group demonstrated severe injury of the intestinal mucosa, lung, kidney, and liver. The intestinal mucosal damage and intestinal barrier dysfunction were obviously attenuated in CDDO-Im-treated group compared with the model group. Also, preconditioning with CDDO-Im reduced pulmonary, hepatic and renal damage, and decreased oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), and NO) and pro-inflammatory responses (tumor necrosis factor (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6)) following I/R injury. Furthermore, we also observed that these protective properties of CDDO-Im were accomplished by the activation of nuclear factor E2-related factor 2 (Nrf2) signaling pathway and upregulation of its downstream antioxidant genes, including heme oxygenase (HO-1), NQO-1, and glutamate–cysteine ligase regulatory subunit (GCLM). Our data suggest that CDDO-Im exerts a beneficial effect on intestinal I/R-associated mucosal barrier dysfunction and distant organ injuries.
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Liu, Caihong, and Qiang Liu. "Community Detection Based on Differential Evolution Using Modularity Density." Information 9, no. 9 (August 30, 2018): 218. http://dx.doi.org/10.3390/info9090218.
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Currently, many community detection methods are proposed in the network science field. However, most contemporary methods only employ modularity to detect communities, which may not be adequate to represent the real community structure of networks for its resolution limit problem. In order to resolve this problem, we put forward a new community detection approach based on a differential evolution algorithm (CDDEA), taking into account modularity density as an optimized function. In the CDDEA, a new tuning parameter is used to recognize different communities. The experimental results on synthetic and real-world networks show that the proposed algorithm provides an effective method in discovering community structure in complex networks.
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Samudio, Ismael, Marina Konopleva, Helene Pelicano, Peng Huang, Olga Frolova, William Bornmann, Yun-ming Ying, Randall Evans, and Michael Andreeff. "A Novel Mechanism of Action of Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me): Direct Permeabilization of the Inner Mitochondrial Membrane To Inhibit Electron Transport and Induce Apoptosis." Blood 106, no. 11 (November 16, 2005): 4462. http://dx.doi.org/10.1182/blood.v106.11.4462.4462.
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Abstract CDDO-Me is a synthetic oleanolic acid derivative that displays antitumorigenic and anti-inflammatory activities, and we have previously reported that this agent potently activates the intrinsic apoptotic pathway in leukemia cells. Here we demonstrate that mitochondrial dysfunction induced by CDDO-Me in leukemia cells is mediated by direct permeabilization of the inner mitochondrial membrane that results in the rapid depletion of mitochondrial glutathione (GSXm), loss of cardiolipin, and inhibition of mitochondrial respiration. More importantly, we demonstrate that in addition to activating the intrinsic apoptotic pathway, the mitochondrial effects of CDDO-Me may mediate its anti-inflammatory activity by modulating the generation of superoxide anion (O2−). Interestingly, CDDO-Me did not increase the generation of O2−, and in fact pretreatment of leukemia cells with CDDO-Me prevented the increase of this reactive oxygen species elicited by inhibition of complex I or III in the absence of de novo protein synthesis. CDDO-Me, but not other inhibitors of respiration, induced a time- and dose-dependent, cyclosporin A-independent permeability transition (mPT) of isolated mitochondria that was sensitive to sulfhydryl antioxidants but not to EDTA. PT induced by CDDO-Me and Ca2+ was accompanied by loss of GSXm suggesting that the increased permeability of the inner mitochondrial membrane facilitates the loss of this antioxidant. Finally, transmission electron microscopy revealed that CDDO-Me rapidly induced caspase-independent mitochondrial swelling and loss of inner membrane structure prior to the release of cytochrome c. Taken together, our results indicate that CDDO-Me is a novel antileukemic agent that induces apoptosis and inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity.
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Kim, Park, Choi, Kong, and Kang. "CDDO-Me Selectively Attenuates CA1 Neuronal Death Induced by Status Epilepticus via Facilitating Mitochondrial Fission Independent of LONP1." Cells 8, no. 8 (August 5, 2019): 833. http://dx.doi.org/10.3390/cells8080833.
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2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that exhibits promising anti-cancer, anti-inflammatory, antioxidant and neuroprotective activities. In addition, CDDO-Me affects cellular differentiation and cell cycle arrest, and irreversibly inhibits Lon protease-1 (LONP1). In the present study, we evaluate the effects of CDDO-Me on mitochondrial dynamics and its downstream effectors in order to understand the underlying mechanism of the neuronal death following status epilepticus (SE, a prolonged seizure activity). CDDO-Me increased dynamin-related proteins 1 (DRP1)-serine 616 phosphorylation via activating extracellular-signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), but not protein kinase A (PKA) or protein phosphatases (PPs). In addition, CDDO-Me facilitated DRP1-mediated mitochondrial fissions, which selectively attenuated SE-induced CA1 neuronal death. Unlike CDDO-Me, LONP1 knockdown led to SE-induced massive degeneration of dentate granule cells, CA1 neurons and hilus interneurons without altering the expression and phosphorylation of DRP1, ERK1/2, JNK and PP2B. LONP1 knockdown could not inhibit SE-induced mitochondrial elongation in CA1 neurons. Co-treatment of CDDO-Me with LONP1 siRNA ameliorated only CA1 neuronal death, concomitant with abrogation of mitochondrial elongation induced by SE. Thus, our findings suggest that CDDO-Me may selectively attenuate SE-induced CA1 neuronal death by rescuing the abnormal mitochondrial machinery, independent of LONP1 activity.
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Holkova, B., S. Kummar, P. Glauber, A. Chen, J. M. Strong, R. J. Parker, J. Collins, A. J. Murgo, J. H. Doroshow, and M. E. Gutierrez. "A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14137. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14137.
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14137 Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m2/hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (Css) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that < 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO Css appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text] No significant financial relationships to disclose.
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Ameen, Azad A., Tarik A. Rashid, and Shavan Askar. "CDDO–HS: Child Drawing Development Optimization–Harmony Search Algorithm." Applied Sciences 13, no. 9 (May 8, 2023): 5795. http://dx.doi.org/10.3390/app13095795.
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Child drawing development optimization (CDDO) is a recent example of a metaheuristic algorithm. The motive for inventing this method is children’s learning behavior and cognitive development, with the golden ratio being employed to optimize the aesthetic value of their artwork. Unfortunately, CDDO suffers from low performance in the exploration phase, and the local best solution stagnates. Harmony search (HS) is a highly competitive algorithm relative to other prevalent metaheuristic algorithms, as its exploration phase performance on unimodal benchmark functions is outstanding. Thus, to avoid these issues, we present CDDO–HS, a hybridization of both standards of CDDO and HS. The hybridized model proposed consists of two phases. Initially, the pattern size (PS) is relocated to the algorithm’s core and the initial pattern size is set to 80% of the total population size. Second, the standard harmony search (HS) is added to the pattern size (PS) for the exploration phase to enhance and update the solution after each iteration. Experiments are evaluated using two distinct standard benchmark functions, known as classical test functions, including 23 common functions and 10 CEC-C06 2019 functions. Additionally, the suggested CDDO–HS is compared to CDDO, the HS, and six others widely used algorithms. Using the Wilcoxon rank-sum test, the results indicate that CDDO–HS beats alternative algorithms.
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Gee, Min Sung, Sung-Bae Kang, Namkwon Kim, Jiyoon Choi, Nam-Jung Kim, Bum-Joon Kim, Kyung-Soo Inn, and Jong Kil Lee. "Bardoxolone Methyl Suppresses Hepatitis B Virus Large Surface Protein Variant W4P-Related Carcinogenesis and Hepatocellular Carcinoma Cell Proliferation Via the Inhibition of Signal Transducer and Activator of Transcription 3 Signaling." Pharmacology 102, no. 1-2 (2018): 105–13. http://dx.doi.org/10.1159/000489998.
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Bardoxolone methyl (CDDO-me) is a synthetic triterpenoid that has been shown to suppress various cancers and inflammation. It has been implicated for the suppression of signal transducer and activator of transcription 3 (STAT3)-mediated signaling, which plays crucial roles in the development and progression of hepatocellular carcinoma (HCC). Previously, we showed that hepatitis B virus (HBV) large surface protein (LHB) variant W4P promotes carcinogenesis and tumor progression through STAT3 activation. Thus, we examined the anti-cancer activity of CDDO-me against HCC using W4P-LHB-expressing NIH3T3 cells and HepG2 and Huh7 HCC cell lines. CDDO-me exerted cytotoxic activity against W4P-LHB-expressing NIH3T3 cells, HepG2 cells, and Huh7 cells, and induced apoptotic cell death in a dose-dependent manner, demonstrating its anti-cancer activity against HCC. Sublethal concentrations of CDDO-me suppressed STAT3 activation by W4P-LHB ectopic expression and interleukin-6 treatment in W4P-LHB-NIH3T3 and Huh7 cells respectively. The suppression of STAT3 activation by CDDO-me in W4P-LHB-NIH3T3 cells was further confirmed by decreased cyclin D1 protein levels and increased p21 and p53 mRNA synthesis. In addition, CDDO-me treatment resulted in decreased cell migration and colony formation in in vitro assays using W4P-LHB-NIH3T3, HepG2, or Huh7 cell lines, supporting its anti-cancer activity through STAT3 inhibition. Furthermore, CDDO-me administration significantly suppressed tumor growth induced by W4P-LHB-expressing NIH3T3 cells in nude mice, confirming its anti-cancer activity. Collectively, our findings demonstrated that CDDO-me is capable of suppressing STAT3 activation in HCC cells and cells transformed by the natural variant of HBV protein. The results suggest that CDDO-me can be a potential therapeutic agent against HCC, especially tumors related to HBV mutations.
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Bernstein, Steven H., Sundararajan Venkatesh, Min Li, Jae Lee, Bin Lu, Shannon P. Hilchey, Kimberly M. Morse, et al. "The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives." Blood 119, no. 14 (April 5, 2012): 3321–29. http://dx.doi.org/10.1182/blood-2011-02-340075.
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Abstract Synthetic triterpenoids are multitarget compounds exhibiting promise as preventative and therapeutic agents for cancer. Their proposed mechanism of action is by forming Michael adducts with reactive nucleophilic groups on target proteins. Our previous work demonstrates that the 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives promote B-lymphoid cell apoptosis through a mitochondria-mediated pathway linked to mitochondrial protein aggregation. As one function of the Lon protease is to eliminate abnormal mitochondrial proteins, we hypothesized that CDDO-induced protein aggregation and lymphoma apoptosis occur by inactivating this enzyme. Here, we show that CDDO and its derivatives directly and selectively inhibit Lon. CDDO blocks Lon-mediated proteolysis in biochemical and cellular assays, but does not inhibit the 20S proteasome. Furthermore, a biotinylated-CDDO conjugate modifies mitochondrial Lon. A striking common phenotype of CDDO-treated lymphoma cells and Lon-knockdown cells is the accumulation of electron-dense aggregates within mitochondria. We also show that Lon protein levels are substantially elevated in malignant lymphoma cells, compared with resting or activated B cells. Finally, we demonstrate that Lon knockdown leads to lymphoma cell death. Together, these findings suggest that Lon inhibition plays a contributory role in CDDO-induced lymphoma cell death, and support the concept that mitochondrial Lon is a novel anticancer drug target.
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Prasad, Dinesh, Kuldeep Panwar, D. R. Bhaskar, and Mayank Srivastava. "CDDITA-Based Voltage-Mode First Order All Pass Filter Configuration." Circuits and Systems 06, no. 11 (2015): 252–56. http://dx.doi.org/10.4236/cs.2015.611025.
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Gleixner, Karoline V., Harald Herrmann, Katharina Blatt, Winfried F. Pickl, Marina Konopleva, Gahininath Y. Bharate, Michael Andreeff, Hiroshi Maeda, and Peter Valent. "The Heat Shock Protein 32 (Hsp32)/HO-1-Targeting Drug SMA-ZnPP and the Triterpenoid CDDO-Me Exert Synergistic Growth-Inhibitory Effects on TKI-Resistant Leukemic Cells in Ph+ CML." Blood 118, no. 21 (November 18, 2011): 4414. http://dx.doi.org/10.1182/blood.v118.21.4414.4414.
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Abstract Abstract 4414 Resistance against one or more tyrosine kinase inhibitors (TKI) prevents eradication of Ph+ chronic myeloid leukemia (CML). In many patients BCR/ABL1 mutations are detectable. We have recently identified two targeted drugs that exert major growth-inhibitory effects on drug-resistant CML cells, the triterpenoid CDDO-Me (Bardoxolone-methyl, REATA Pharma) that blocks several signalling molecules including mTOR, Akt, and STAT3, and upregulates expression of heat shock protein 32 (Hsp32 = heme oxygenase 1, HO-1), and styrene-maleic acid-copolymer micelle-encapsulated ZnPP (SMA-ZnPP), a water-soluble inhibitor of Hsp32/HO-1. In the current project, we asked whether CDDO-Me exerts inhibitory effects on growth of TKI-resistant CML cells and whether the combination of CDDO-Me and SMA-ZnPP would produce synergistic effects in drug-resistant CML cells. As determined by 3H-thymidine incorporation, CDDO-Me was found to inhibit the proliferation of imatinib-responsive and imatinib-resistant K562, imatinib-resistant KCL-22, KU812, and Ba/F3 cells transfected with various TKI-resistant mutants of BCR/ABL1 (T315I, E255K, Y253F, H396P). In each case, IC50 values <1 μM were obtained without major differences between imatinib-responsive and imatinib-resistant cells. Growth-inhibition was accompanied by apoptosis as assessed by combined AnnexinV/PI staining as well as by an increase in expression of HO-1 in KU812 and KCL-22 cells. CDDO-Me was also found to inhibit proliferation of leukemic cells in all patients with TKI-resistant CML (n=4), with IC50 values ranging between <0.1 and 0.5 μM. No differences in IC50 values were observed between treatment-naïve and TKI-resistant cells. Next, we applied the combination CDDO-Me+SMA-ZnPP and found that this combination acts highly synergistically on imatinib-responsive and imatinib-resistant K562 cells as well as primary CML cells isolated from imatinib-naïve CML patients (n=2) or from patients with imatinib-resistant CML (n=2), including one patient in whom BCR/ABL1 T315I was detected. We also examined whether CDDO-Me would exert synergistic effects on CML cells when combined with BCR/ABL1 TKI. In these experiments, we applied the combinations CDDO-Me+dasatinib and CDDO-Me+nilotinib on K562 cells. Both combinations were found to synergistically induce growth inhibition. In conclusion, CDDO-Me inhibits the proliferation of imatinib-resistant BCR/ABL1+ cells, including primary CML cells isolated from untreated patients and cells derived from patients with TKI-resistant CML carrying the BCR/ABL1 mutant T315I. Our data also show that CDDO-Me + SMA-ZnPP and CDDO-Me + BCR/ABL1 TKI synergize in producing growth inhibition in CML cells. Whether these drug combinations also produce synergistic effects in vivo in patients with TKI-resistant CML remains to be evaluated. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.
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Khurana, Namrata, Partha K. Chandra, Hogyoung Kim, Asim B. Abdel-Mageed, Debasis Mondal, and Suresh C. Sikka. "Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells." Antioxidants 9, no. 1 (January 12, 2020): 68. http://dx.doi.org/10.3390/antiox9010068.
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Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.
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Lin, Xun, Suzanne Tawch, Stephen Gaudino, Suyasha Roy, Patricia Castillo, Waleed Abdel Wahab Elsegeiny, Nobunao Wakabayashi, et al. "Nrf2 differentially regulates pro- and anti-inflammatory function of Th17 cells through RORγT, SOD3 and Ahr." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 59.34. http://dx.doi.org/10.4049/jimmunol.204.supp.59.34.
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Abstract IL-17A and IL-22 derived from CD4+ T cells are significant for both inflammatory and tissue protective responses. However, it remains unclear whether IL-17A and IL-22 can be regulated differently to achieve targeted functional outcome. Here, we showed that Nrf2 selectively regulated IL-17A and IL-22 responses in CD4+ T cells. Nrf2−/− mice challenged with Ovalbumin (Ova) + LPS displayed reduced IL-22 but enhanced IL-17A response. Interestingly, CDDO-Im, a selective Nrf2 activator, induced IL-22 but suppressed IL-17A response in CD4+ T cells polarized under Th17 cell condition. CDDO-Im-activated CD4+ T cells had lower Rorc, but increased Cybb, Sod1 and Sod3 transcript. Luciferase reporter assay showed that IL-17A promoter activity is inhibited by Nrf2 at the presence of RORγT, suggesting that inhibition of IL-17A by Nrf2 is RORγT-dependent. CDDO-Im-impaired IL-17A response was also abolished in SOD3−/−, showing that SOD3 is involved in CDDO-Im-mediated inhibition of IL-17A. Furthermore, we found that CDDO-Im induced aryl hydrocarbon receptor (Ahr) and its downstream Cyp1a1 and Cyp1b1 gene expression. Additionally, CDDO-Im induced Nqo1 expression, an Nrf2-activated gene, in WT mice but not in Ahr−/− mice. CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in Ahr−/− mice, supporting that Ahr is involved in the induction of IL-22 by Nrf2. Finally, upon the stimulation of anti-CD3 and anti-CD28, CDDO-Im also mediated the inhibition of IL-17A but induction of IL-22 production in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, our data show that Nrf2 promotes IL-22 production via Ahr, whereas RORγT and SOD3 are involved in Nrf2-mediated inhibition of IL-17A expression in Th17 cells.
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Bernstein, Steven H., Bin Lin, Shannon Hilchey, N. Villaluna, L. Chen, K. Madura, Kim Morse, et al. "The Triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid and Its Derivatives Inhibit Mitochondrial Lon Protease Activity: A Potential Novel Pathway for the Induction of Lymphoma Cell Death." Blood 114, no. 22 (November 20, 2009): 414. http://dx.doi.org/10.1182/blood.v114.22.414.414.
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Abstract Abstract 414 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its C(28) imidazole and methylester derivatives are novel oleanane triterpenoids exhibiting promise as both therapeutic and preventative agents for cancer. We have previously shown that these synthetic triterpenoids promote lymphoma cell death through a novel mitochondria-mediated mechanism whereby mitochondrial protein thiols are modified resulting in the formation of mitochondrial protein aggregates leading to apoptotic cell death (Cancer Res. 2007; 67:4). As mitochondrial Lon is a critical quality control protease that prevents the toxic accumulation and aggregation of damaged mitochondrial proteins we hypothesized that one effect of the triterpenoids might be to inhibit Lon-mediated proteolysis. Herein we show that CDDO and its derivatives inhibit purified Lon protease. In particular, the imidazole and methylester derivatives of CDDO (CDDO-Im and CDDO-Me) are more effective inhibitors of Lon than CDDO. Interestingly, these derivatives are also more potent inducers of lymphoma cell death than CDDO. We also show that CDDO-Me inhibits cellular mitochondrial Lon, as determined by its ability to inhibit the degradation of the Mitochondrial Transcription Factor A (TFAM), an endogenous Lon protein substrate. To exclude the possibility that the triterpenoid mediated inhibition of TFAM degradation is mediated by the cytoplasmic proteasome, we show that the triterpenoids have no effect on proteasome-mediated proteolysis. To determine the mechanism through which the triterpenoids block Lon activity, we next used a biotinylated-CDDO derivative and showed that this derivative forms adducts with Lon, suggesting that the triterpenoids directly inhibit the protease in cells. In contrast, the biotinylated-CDDO derivative did not form adducts with other proteins, such as the mitochondrial ClpP protease, TFAM, or the endoplasmic reticulum protein BiP, suggesting a level of specificity for triterpenoid adduct formation. Indeed, the formation of protein adducts with Lon is consistent with the fact that the triterpenoids contain a Michael Addition moiety which allows it to form adducts with both protein and non-protein thiols. Consistent with the inhibitory effects of the triterpenoids on mitochondrial Lon protease activity, CDDO-treated lymphoma cells exhibit striking electron dense inclusions within mitochondria, but not the cytosol or other cellular compartments. Similar inclusions within mitochondria are also seen in a Lon knockdown cell line, in which a short hairpin RNA targeting Lon mRNA is inducibly expressed in LS174 colon cancer cells upon treatment with doxycycline. This finding supports the notion that the CDDO-induced inclusions are due, in part, to inhibition of Lon protease activity. Furthermore, we show that Lon protein expression levels are higher in both malignant lymphoma cell lines and patient derived biopsy specimens, as compared to that seen in resting or activated normal B cells. Taken together, these results suggest that; (a) the mitochondrial ATP-dependent Lon protease is a new target of synthetic triterpenoids, and; (b) Lon may be a novel and viable target for cancer therapeutics. Supported by an NCI SPORE grant in lymphoma 1P50 CA130805. Disclosures: Bernstein: millenium: Consultancy; genentech: Consultancy, Speakers Bureau; enzon: Consultancy.
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Suh, N., S. Paul, H. J. Lee, T. Yoon, N. Shah, A. I. Son, A. H. Reddi, D. Medici, and M. B. Sporn. "RETRACTED: Synthetic triterpenoids, CDDO-Imidazolide and CDDO-Ethyl amide, induce chondrogenesis." Osteoarthritis and Cartilage 20, no. 5 (May 2012): 446–50. http://dx.doi.org/10.1016/j.joca.2012.01.018.
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Moerland, Jess Ann, and Karen T. Liby. "Abstract 3534: The triterpenoid CDDO-Me redirects macrophage polarization and decreases tumor burden in a preclinical model of NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3534. http://dx.doi.org/10.1158/1538-7445.am2022-3534.
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Abstract The NRF2/KEAP1 pathway regulates cytoprotective mechanisms that protect healthy cells from malignant transformation and maintain cellular homeostasis. Up to 30% of human lung tumors contain a mutation that results in constitutive NRF2 pathway activation, which contributes to cancer cell survival, disease progression, and resistance to chemotherapies. However, the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages in lung cancers contribute to cancer progression or regression depending on the context, and NRF2 activity affects macrophage activation and trafficking. To evaluate the role of NRF2 activity in macrophages, bone marrow-derived macrophages (BMDMs) from NRF2 wild-type (WT) and knockout (KO) mice were treated to induce anti-tumor (M1), tumor-promoting (M2), and tumor-educated macrophage phenotypes and then treated with the potent NRF2 activator CDDO-Methyl ester (CDDO-Me), also known as bardoxolone methyl. In tumor-educated BMDMs isolated from NRF2 WT mice and cultured in conditioned media from lung cancer cells, CDDO-Me (100 nM) induced a 3-fold increase in mRNA expression of the M1 markers TNF-α and IL-6. The expression of these cytokines was not increased by CDDO-Me in tumor-educated BMDMs isolated from NRF2 KO mice. CDDO-Me also decreased mRNA expression of the angiogenic factor VEGF and the chemokine CCL2 in tumor-educated BMDMs isolated from WT but not NRF2 KO mice. VEGF is expressed by tumor-promoting macrophages and CCL2, a chemotactic factor that recruits M2 macrophages into the lung, is a biomarker of poor prognosis in lung cancer patients. CDDO-Me has potent anti-tumor effects in the A/J mouse model of non-small cell lung cancer (NSCLC), but the mechanism of these effects was unknown. To evaluate, A/J WT and NRF2 KO A/J mice were injected with vinyl carbamate to initiate lung tumors. Two weeks later, mice were fed either a control diet or a diet containing CDDO-Me (50 mg/kg diet: ~12.5 mg/kg body weight) for 16 weeks. Ultrasound confirmed the development of tumors in the lungs of mice throughout the study, and differences in tumor number and lung parenchyma structure were detected at 15 weeks of treatment. CDDO-Me significantly (p<0.05) decreased tumor burden in WT A/J mice. Tumor burden in the NRF2 KO mice was significantly (p<0.05) higher than in WT mice, irrespective of treatment. Tumor count in NRF2 KO A/J mice treated with either vehicle or CDDO-Me was increased 2-fold compared to WT A/J mice on the vehicle control diet. These data show that CDDO-Me promotes an anti-cancer macrophage phenotype in vitro that is dependent on NRF2 activation. Additionally, NRF2 KO increases lung tumor burden in the A/J model of NSCLC and CDDO-Me significantly decreases tumor burden in A/J mice in a NRF2-dependent manner. Future studies will test the effect of CDDO-Me and NRF2 activity on the lung tumor immune microenvironment in vivo. Citation Format: Jess Ann Moerland, Karen T. Liby. The triterpenoid CDDO-Me redirects macrophage polarization and decreases tumor burden in a preclinical model of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3534.
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Kim, Ji-Eun, Hana Park, Ji-Eun Lee, and Tae-Cheon Kang. "CDDO-Me Inhibits Microglial Activation and Monocyte Infiltration by Abrogating NFκB- and p38 MAPK-Mediated Signaling Pathways Following Status Epilepticus." Cells 9, no. 5 (May 1, 2020): 1123. http://dx.doi.org/10.3390/cells9051123.
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Following status epilepticus (SE, a prolonged seizure activity), microglial activation, and monocyte infiltration result in the inflammatory responses in the brain that is involved in the epileptogenesis. Therefore, the regulation of microglia/monocyte-mediated neuroinflammation is one of the therapeutic strategies for avoidance of secondary brain injury induced by SE. 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), which regulates intracellular redox homeostasis. In addition, CDDO-Me has anti-inflammatory properties that suppress microglial proliferation and its activation, although the underlying mechanisms have not been clarified. In the present study, CDDO-Me ameliorated monocyte infiltration without vasogenic edema formation in the frontoparietal cortex (FPC) following SE, accompanied by abrogating monocyte chemotactic protein-1 (MCP-1)/tumor necrosis factor-α (TNF-α) expressions and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. Furthermore, CDDO-Me inhibited nuclear factor-κB (NFκB)-S276 phosphorylation and microglial transformation, independent of Nrf2 expression. Similar to CDDO-Me, SN50 (an NFκB inhibitor) mitigated monocyte infiltration by reducing MCP-1 and p38 MAPK phosphorylation in the FPC following SE. Therefore, these findings suggest, for the first time, that CDDO-Me may attenuate microglia/monocyte-mediated neuroinflammation via modulating NFκB- and p38 MAPK-MCP-1 signaling pathways following SE.
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Amirova, Kristiana M., Petya A. Dimitrova, Milena N. Leseva, Ivanka K. Koycheva, Albena T. Dinkova-Kostova, and Milen I. Georgiev. "The Triterpenoid Nrf2 Activator, CDDO-Me, Decreases Neutrophil Senescence in a Murine Model of Joint Damage." International Journal of Molecular Sciences 24, no. 10 (May 15, 2023): 8775. http://dx.doi.org/10.3390/ijms24108775.
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The synthetic 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a potent activator of the erythroid 2-p45-derived factor 2, Nrf2, a leucine-zipper regulator of the antioxidant response. Herein, we investigated the effect of CDDO-Me on neutrophil function in a murine model of joint damage. Collagenase-induced osteoarthritis (CIOA) was initiated by the intra-articular injection of collagenase in the knee-joint cavity of Balb/c mice. CDDO-Me was administrated intra-articularly twice a week starting at day 7 post-CIOA, and its effect was evaluated at day 14. Neutrophils in blood and bone marrow (BM), cell apoptosis, necrosis, expression of C-X-C chemokine receptor 4 (CXCR4), beta-galactosidase (β-Gal), and Nrf2 levels were measured by flow cytometry. In vitro, CDDO-Me promoted cell survival, reduced cell necrosis, and increased Nrf2 levels by 1.6 times. It decreased surface CXCR4 expression and reduced the frequency of senescent β-Gal+CXCR4+ neutrophils by three times. In vivo, the degree of knee-joint damage in CIOA was correlated with upregulated CXCR4 on CD11b+ neutrophils. CDDO-Me improved the disease histological score, increased the levels of Nrf2, and downregulated surface CXCR4 on mature BM cells. Our data suggest that CDDO-Me may act as a potent regulator of neutrophil senescence during the progression of knee-joint damage.
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Siracusa, Rosalba, Ramona D’Amico, Marika Cordaro, Alessio Filippo Peritore, Tiziana Genovese, Enrico Gugliandolo, Rosalia Crupi, et al. "The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways." International Journal of Molecular Sciences 22, no. 8 (April 13, 2021): 3991. http://dx.doi.org/10.3390/ijms22083991.
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Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways.
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Pedersen, Irene M., Shinichi Kitada, Aaron Schimmer, Youngsoo Kim, Juan M. Zapata, Lula Charboneau, Laura Rassenti, et al. "The triterpenoid CDDO induces apoptosis in refractory CLL B cells." Blood 100, no. 8 (October 15, 2002): 2965–72. http://dx.doi.org/10.1182/blood-2002-04-1174.
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Chronic lymphocytic leukemia (CLL) cells develop chemo-resistance over time. Most anticancer agents function through induction of apoptosis, and therefore resistance against these agents is likely to be caused by selection for CLL cells with defects in the particular apoptosis pathway that is triggered by these drugs. Anticancer agents that function through alternative apoptotic pathways might therefore be useful in treating chemo-resistant CLL. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity. We examined the effects of CDDO (triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) on CLL B cells in vitro. CDDO induced apoptosis in a dose-dependent manner in all (n = 30) CLL samples tested, including previously untreated and chemo-resistant CLL specimens. CDDO induced rapid proteolytic processing of caspase-8, but not caspase-9, in CLL B cells, suggesting activation of a mitochondria-independent pathway. CDDO-induced apoptosis of CLL B cells was blocked by cytokine response modifier A (CrmA), a suppressor of caspase-8, but not by X-linked inhibitor of apoptosis protein–baculovirus IAP repeat–3 (XIAP-BIR3), a fragment of XIAP, which selectively inhibits caspase-9. Examination of CDDO effects on expression of several apoptosis-relevant genes demonstrated significant reductions in the levels of caspase-8 homolog Fas-ligand interleukin-1–converting enzyme (FLICE)–inhibitory protein (c-FLIP), an endogenous antagonist of caspase-8. However, reductions of FLIP achieved by FLIP antisense oligonucleotides were insufficient for triggering apoptosis, indicating that CDDO has other targets in CLL B cells besides FLIP. These data suggest that the synthetic triterpenoid CDDO should be further explored as a possible therapeutic agent for treatment of chemo-resistant CLL.
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Lin, Xun, Stephen Gaudino, Jay Kolls, and Pawan Kumar. "Nrf2 selectively regulates IL-22 and IL-17A production in Th17 cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 181.7. http://dx.doi.org/10.4049/jimmunol.202.supp.181.7.
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Abstract Th17 cell-derived IL-17A and IL-22 are critical for mounting both inflammatory and tissue protective responses. It remains unclear whether cytokine responses can be modified differently to achieve targeted functional outcome. A therapeutic strategy which inhibits CD4+ T cell-derived inflammatory IL-17A responses but concomitantly promotes IL-22-dependent tissue protective or regenerative response is of great clinical significance. Here, we showed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) selectively regulated IL-17A and IL-22 responses in CD4+ T cells. We found that Nrf2−/− mice had reduced IL-22 responses in Ovaalbumin (Ova) + LPS and separately concanavalin A (Con A) administered mice. Furthermore, CDDO-Im, a selective Nrf2 activator, induced IL-22 but suppressed IL-17A response in CD4+ T cells polarized under Th17 cell condition. Our qPCR data revealed that CDDO-Im-activated CD4+ T cells had lower Rorc, but increased Cybb, Sod1 and Sod3 transcript. The expression pattern of Il23r and Sod2 was unaltered. CDDO-Im-dependent IL-17A but not IL-22 response was regulated by Sod3. Interestingly, we found that CDDO-Im induced aryl hydrocarbon receptor (Ahr) and its downstream Cyp1a1 and Cyp1b1 gene expression. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity in a dose-dependent manner. Additionally, CDDO-Im induced Nqo1 expression, a Nrf2-activated gene, in WT mice but not in Ahr−/− mice. Finally, we confirmed that the CDDO-Immediated induction of IL-22 production in CD4+ T cells was abrogated in Ahr−/− mice. Collectively, our data show that Nrf2 promotes IL-22 production while it inhibits IL-17A expression in Th17 cells.
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Casares, Laura, Rita Moreno, Kevin X. Ali, Maureen Higgins, Sharadha Dayalan Naidu, Graham Neill, Lena Cassin, et al. "The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity." Redox Biology 51 (May 2022): 102291. http://dx.doi.org/10.1016/j.redox.2022.102291.
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Moerland, Jess Ann, and Karen T. Liby. "Abstract 5176: CDDO-methyl ester redirects macrophage polarization and reduces lung tumor burden in a Nrf2-dependent manner." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5176. http://dx.doi.org/10.1158/1538-7445.am2023-5176.
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Abstract The cytoprotective Nrf2 pathway impacts immune cell function and has been proposed as a target for many inflammation-related diseases, but the effects of Nrf2 activation on immune cells in the cancer context are not well characterized. With Nrf2 activators under development and in clinical trials, it is critical to understand the influence of these drugs on cancer progression. While the anti-inflammatory nature of Nrf2 activation protects healthy cells from malignant transformation, cancer cells can utilize the pathway to promote resistance to anti-cancer drugs and increase tumor cell survival. Up to 30% of human lung adenocarcinomas acquire mutations in the Nrf2 pathway which result in constitutive activation. However, triterpenoids, including CDDO-methyl ester (CDDO-Me, also known as bardoxolone methyl), are potent pharmacological Nrf2 activators with demonstrated anti-cancer activity in preclinical models. Lung cancer is the leading cause of cancer-related mortality worldwide, and macrophages are the most common immune cell type in the lung tumor microenvironment. To investigate Nrf2 activation in macrophages in the context of lung cancer, bone marrow-derived macrophages (BMDMs) were isolated from wild type (WT) and Nrf2 knock out (KO) mice and cultured in conditioned media from lung cancer cells to produce a tumor-educated phenotype. The triterpenoid CDDO-Me had anti-inflammatory effects in BMDMs stimulated with the conventional cytokines IFN-γ and LPS. Conversely, CDDO-Me increased (p < 0.05) the M1 macrophage markers TNFα, IL-6, and MHC-II and decreased the M2 macrophage markers VEGF, CCL2, and CD206 in tumor-educated BMDMs in a Nrf2-dependent manner. The phenotypic changes were observed on transcription, protein, and surface marker levels. This context-dependent reversal of BMDM polarization suggests that Nrf2 activation has different outcomes in different environments. To test CDDO-Me in vivo, lung tumors were initiated with vinyl carbamate in A/J WT and Nrf2 KO mice, and animals were fed either control diet or CDDO-Me (12.5-50 mg/kg of diet) for 16 weeks. CDDO-Me significantly (p < 0.05) decreased tumor number, size, and overall burden and reduced the histopathological severity of tumors in a Nrf2- and dose-dependent manner. Additionally, CDDO-Me increased the infiltration of CD64+ macrophages but decreased CD206+ expression in macrophages in the lungs of WT tumor-bearing mice. Interestingly, CD206 expression was higher on macrophages in the spleen of WT mice treated with CDDO-Me, suggesting a cancer context dependency. Future studies will evaluate the dependency of Nrf2 activation in macrophages for the anti-tumor activity of CDDO-Me. Citation Format: Jess Ann Moerland, Karen T. Liby. CDDO-methyl ester redirects macrophage polarization and reduces lung tumor burden in a Nrf2-dependent manner. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5176.
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Kim, Ji-Eun, and Tae-Cheon Kang. "CDDO-Me Attenuates Astroglial Autophagy via Nrf2-, ERK1/2-SP1- and Src-CK2-PTEN-PI3K/AKT-Mediated Signaling Pathways in the Hippocampus of Chronic Epilepsy Rats." Antioxidants 10, no. 5 (April 23, 2021): 655. http://dx.doi.org/10.3390/antiox10050655.
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Clasmatodendrosis is an autophagic astroglial death showing extensive swollen cell bodies with vacuoles and disintegrated/beaded processes. This astroglial degeneration is closely relevant to the synchronous epileptiform discharges. However, the underlying molecular mechanisms and the roles of clasmatodendrosis in spontaneous seizure activity are still unknown. The 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is one of the activators for nuclear factor-erythroid 2-related factor 2 (Nrf2) that is a redox-sensitive transcription factor. In the present study, we explored the effects of CDDO-Me on clasmatodendrosis in chronic epilepsy rats, which could prevent epilepsy-related complications. In the present study, clasmatodendritic astrocytes showed reduced Nrf2 expression and its nuclear accumulation, which were restored by CDDO-Me. CDDO-Me also abrogated heat shock protein 25 (HSP25) upregulation in clasmatodendritic astrocytes by regulating extracellular signal-related kinases 1/2 (ERK1/2)-specificity protein 1 (SP1)- and Src-casein kinase 2 (CK2)-phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-phosphatidylinositol-3-kinase (PI3K)-AKT-glycogen synthase kinase 3β (GSK3β)-bax-interacting factor 1 (Bif-1)-mediated signaling pathways in chronic epilepsy rats. In addition, CDDO-Me ameliorated spontaneous seizure duration, but not seizure frequency and behavioral seizure severity. Therefore, our findings suggest that clasmatodendrosis may affect seizure duration in chronic epilepsy rats, and that CDDO-Me may attenuate autophagic astroglial degeneration by regulating various signaling pathways.
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Santiesteban, Gretel Maria Torres, Tamer Shabaneh, Rajan Bhandari, Karen Liby, Mary Jo Turk, and Patricia Pioli. "CDDO-Me Redirects Macrophage Activation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 135.17. http://dx.doi.org/10.4049/jimmunol.202.supp.135.17.
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Abstract Melanoma tumors are highly immunogenic, making them an attractive target for immunotherapy. However, many patients do not mount robust clinical responses to targeted therapies, which is attributable, at least in part, to suppression of immune responses by tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Using a human in vitro culture system, we now show that the synthetic triterpenoid CDDO-Me enhances immune activation by reprogramming macrophages from immuno-suppressive to immuno-stimulatory. CDDO-Me treatment inhibits surface marker expression of CD16 and CD163 and significantly reduces production of CCL2 and IL-6 in macrophages. These studies also demonstrate that CDDO-Me effects on TAM activation are enhanced when macrophages are tri-cultured with autologous activated T cells and BRAFV600Emutant cells. Because CDDO-Me dramatically attenuates secretion of CCL2, we hypothesize that CDDO-Me may enhance melanoma patient response to additional immunotherapies, including BRAF inhibition. Approximately 50% of advanced melanomas harbor activating BRAFV600Emutations, and BRAF inhibitors have consistently shown anti-tumor responses in patients with BRAFV600Emutant melanoma. However, the duration of the response has been limited due to the development of acquired resistance, which occurs because of myeloid recruitment driven by CCL2. Current studies are focused on assessing the efficacy of combination CDDO-Me/BRAF inhibition. Collectively, these studies suggest that the redirection of immuno-suppressive myeloid cell activation may provide both a direct means of inhibiting melanoma growth and may enhance the efficacy of additional targeted immunotherapies.