2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid and Related Compounds Inhibit Growth of Colon Cancer Cells through Peroxisome Proliferator-Activated Receptor γ-Dependent and -Independent Pathways

Chintharlapalli, Sudhakar; Papineni, Sabitha; Konopleva, Marina; Andreef, Michael; Samudio, Ismael; Safe, Stephen

doi:10.1124/mol.105.011437

Cited by 79 publications

(88 citation statements)

References 27 publications

(31 reference statements)

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“…This difference in tissue/cell selectivity between CDDO and thiazolidinediones in their PPARg-dependent responses may result from the unique ability of CDDO to recruit different classes of coactivators. As such, our data in colon cancer cells showed recruitment of multiple coactivators (Src-1, Src-2, Src-3, TRAP220/DRIP205, CARM-1, and PGC-1) that is qualitatively different from that induced by other PPARg ligands (41).…”

Section: Discussionmentioning

confidence: 87%

“…Because caveolin-1 exhibits tumor-suppressing and growth-inhibitory activities, these results suggest that the induction of caveolin-1 is important for the antiproliferative effects of PPARg-active CDDO in breast cancer. We have recently reported that CDDOinduced growth inhibition of colon cancer cell correlated with induction of caveolin-1 in PPARg-dependent fashion (41). Further studies will need to be done to determine whether the induction of caveolin-1 by CDDO is responsible for the inhibition of HER2 tyrosine activity and cyclin D1 down-regulation.…”

Section: Discussionmentioning

confidence: 99%

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Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells

Konopleva¹,

Zhang²,

Shi³

et al. 2006

Molecular Cancer Therapeutics

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HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growthinhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer. Both cell growth and colony formation in the soft agar assay, a hallmark of the transformation phenotype, were preferentially suppressed in HER2-overexpressing cell lines at low concentrations of CDDO, whereas growth-inhibitory effects at high concentrations did not correlate with the expression level of HER2. CDDO dose-dependently inhibited phosphorylation of HER2 in HER2-overexpressing cells and diminished HER2 kinase activity in vitro. CDDO induced the transactivation of the nuclear receptor peroxisome proliferator-activated receptor-; in both vector control and HER2-transfected MCF7 cells. Dose-response studies showed that the growth inhibition seen at lower concentrations of CDDO correlated with induction of the tumor suppressor gene caveolin-1, which is known to inhibit breast cancer cell growth. CDDO also reduced cyclin D1 mRNA and protein expression. In vivo studies with liposomally encapsulated CDDO showed complete abrogation of the growth of the highly tumorigenic MCF7/HER2 cells in a xenograft model of breast cancer. These findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer. [Mol Cancer Ther 2006;5(2):317 -28]

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells

Konopleva¹,

Zhang²,

Shi³

et al. 2006

Molecular Cancer Therapeutics

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“…44 Another study by Chintharlapalli et al found that CDDO-Im showed higher activity to induce PPARgamma interactions with the corepressor SMRT than CDDO. 45 CDDO induced the transcriptionally active isoform of CEBPA (p42), increased the p42/p30 ratio, and enhanced CEBPA DNA-binding activity ( Figures 3D and 4A-C). Importantly, CDDO partially restored granulocytic maturation of differentiation-arrested BCR/ABL-expressing cells and rescued p42 CEBPA expression from a construct bearing the uORF/spacer region of CEBPA 5ЈUTR.…”

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confidence: 99%

“…on August 28, 2018. by guest www.bloodjournal.org From CDDO and CDDO-Im have been described earlier. 1,44,45 In a previous report, CDDO-Im but not CDDO induced the monocytic marker CD36, 1,17 suggesting that the CDDO derivatives may induce qualitatively different patterns of myelomonocytic differentiation. In addition, while CDDO acted as a partial agonist for the PPARgamma receptor, another close relative, CDDO-Me, which binds to PPARg with similar affinity, is an antagonist.…”

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confidence: 99%

CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer–binding protein alpha

Koschmieder

D’Alo’

Radomska

et al. 2007

Blood

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IntroductionThe triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives, CDDO-methylester (CDDO-Me) and CDDO-imidazole (CDDO-Im), induce growth arrest and apoptosis of a variety of solid tumor and leukemic cell lines in vitro and in vivo. 1,2 Different signaling pathways account for the proapoptotic and antiproliferative effects of CDDO. CDDO induces apoptosis through both caspase-independent and -dependent mechanisms, the latter involving caspase-8 activation, Bid cleavage, cytochrome c release, and caspase-3 activation. [3][4][5][6] Furthermore, JNK, p38, and ERK pathways are involved in CDDO-induced apoptosis of tumor cell lines 7-9 mediated by disrupted intracellular redox balance and involving decreased glutathione and increased reactive oxygen species [9][10][11][12] CDDO-induced growth arrest of breast cancer cell lines correlates with transactivated PPARgamma and leads to up-regulation of p21 cip1waf1 , GADD153, CCAAT enhancer-binding proteins (CEBPs), and proteasome-regulatory factors, and to down-regulation of cyclin D1, PCNA, and IRS1. 13 CDDO and CDDO-Im activate the TGF␤ pathway through activation of Smad2/3,14,15 which is required for the repression of inflammatory molecules by CDDO. 16 Interestingly, CDDO and its derivatives also induce differentiation of leukemic cells. 1,2,7,17 Differentiation of normal hematopoietic stem cells into their mature progeny critically depends on a fine-tuned interplay of hematopoietic transcription factors. 18 Among these, we have recently shown that increased CEBP beta (CEBPB) expression is critical for CDDO-Im-induced monocytic differentiation, and this was partially dependent upon ERK activation and TGF␤-mediated Smad activation. 17 Granulocytic differentiation requires the presence of functional CEBPA, since mice with a targeted disruption of the CEBPA gene demonstrate a selective lack of granulocytes and an accumulation of immature myeloid cells. 19 The expression and/or function of CEBPA is severely altered in a significant fraction of acute myeloid leukemia (AML) subtypes. 20,21 CEBPA is mutated in 7% of all AML cases with normal cytogenetics, and this results in a balance shift from the transcriptionally active full-length isoform (p42) toward the dominantnegatively acting p30 isoform. 22 The fusion protein AML1-ETO suppresses CEBPA transcription, 23 and AML1-MDS1-EVI1 and CBFB-SMMHC oncogenes inhibit CEBPA translation through activation of the RNA-binding protein calreticulin. 24,25 In these AML subtypes, re-expression of functional CEBPA restores granulocytic differentiation, suggesting that suppression of CEBPA is essential for the phenotype of AML blasts. Likewise, differentiation of myeloid progenitors in chronic myelogenous leukemia The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use...

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“…In addition, they were found to inhibit proliferation, and induce differentiation and apoptosis in cancer cells in vitro. They have also been shown to inhibit carcinogen-induced primary tumor growth, orthotopic and ectopic tumor formation, as well as lung metastasis and in multiple experimental animal models (11,12,(17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

The Acetylenic Tricyclic Bis(cyano enone), TBE-31 Inhibits Non–Small Cell Lung Cancer Cell Migration through Direct Binding with Actin

Chan

Saito²,

Honda

et al. 2014

Cancer Prevention Research

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The migratory and invasive potential of the epithelial-derived tumor cells depends on epithelial-tomesenchymal transition (EMT) as well as the reorganization of the cell cytoskeleton. Here, we show that the tricyclic compound acetylenic tricyclic bis(cyano enone), TBE-31, directly binds to actin and inhibits linear and branched actin polymerization in vitro. Furthermore, we observed that TBE-31 inhibits stress fiber formation in fibroblasts as well as in non-small cell lung cancer cells during TGFb-dependent EMT. Interestingly, TBE-31 does not interfere with TGFb-dependent signaling or changes in E-cadherin and Ncadherin protein levels during EMT. Finally, we observed that TBE-31 inhibits fibroblast and non-small cell lung tumor cell migration with an IC 50 of 1.0 and 2.5 mmol/L, respectively. Taken together, our results suggest that TBE-31 targets linear actin polymerization to alter cell morphology and inhibit cell migration. Cancer Prev Res; 7(7); 727-37. Ó2014 AACR.

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2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid and Related Compounds Inhibit Growth of Colon Cancer Cells through Peroxisome Proliferator-Activated Receptor γ-Dependent and -Independent Pathways

Cited by 79 publications

References 27 publications

Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells

Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells

CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer–binding protein alpha

The Acetylenic Tricyclic Bis(cyano enone), TBE-31 Inhibits Non–Small Cell Lung Cancer Cell Migration through Direct Binding with Actin

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