2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis

Couch, Robin D.; Ganem, Neil J.; Zhou, Ming; Popov, Veljko M.; Honda, Tadashi; Veenstra, Timothy D.; Sporn, Michael B.; Anderson, Amy C.

doi:10.1124/mol.105.018572

Cited by 17 publications

(9 citation statements)

References 43 publications

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“…At higher concentrations, CDDO-Im may bind to reactive cysteine residues on other target proteins, such as IKK, to induce apoptosis. Interestingly, all the direct targets of CDDO-Im and its analogues identified to date, including PPARg, Keap1, and h-tubulin, contain reactive cysteine residues, which play a critical role in the cellular function of the respective proteins (4,18,22). In our current studies, we have identified Cys 179 on IKK as a critical target of CDDO-Im.…”

Section: Discussionmentioning

confidence: 59%

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β

Yore¹,

Liby²,

Honda

et al. 2006

Molecular Cancer Therapeutics

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110

107

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The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1, 9(11)-dien-28-oyl]imidazole (CDDO-Im) is a multifunctional agent with potent anti-inflammatory, antiproliferative, cytoprotective, and apoptotic activities, whose molecular targets are unknown. Using both cell-free and cellular assays, we show that CDDO-Im is a direct inhibitor of IKB kinase (IKK) B and that it thereby inhibits binding of nuclear factor-KB to DNA and subsequent transcriptional activation. Pretreatment of cells with CDDO-Im prevents IKBA phosphorylation and degradation in response to tumor necrosis factor A. The kinetics of this inhibition by CDDOIm are rapid and occur within 15 min. A biotinylated analogue of CDDO-Im showed that CDDO-Im binds to the IKK signalsome. Furthermore, we show that Cys 179 on IKK is a target for CDDO-Im. This is the first report to show that this novel synthetic triterpenoid binds to and inhibits IKKB directly. [Mol Cancer Ther 2006;5(12):3232 -9]

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Section: Discussionmentioning

confidence: 59%

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β

Yore¹,

Liby²,

Honda

et al. 2006

Molecular Cancer Therapeutics

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110

107

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“…Mitochondrial glutathione , the mitochondrial protease Lon (Bernstein et al, 2012), and a limited number of thiolcontaining mitochondrial proteins (Brookes et al, 2007) have also been studied using a biotinylated triterpenoid. The SOs also directly interact with tubulin and actin (Couch et al, 2006;, but the physiological consequences of these interactions are less apparent because very high concentrations of SOs (30 -50 M) are required to disrupt polymerization of these proteins. Moreover, mere interaction of a protein with a biotinylated SO does not ensure functionality.…”

Section: H Thiol Proteomementioning

confidence: 99%

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

2012

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“…To test whether CDDO forms adducts with Lon, we used a biotinylated conjugate of CDDO (CDDO biotin ), which has comparable activity to its parent compound albeit with reduced potency, 26,40 and which colocalizes with mitochondria. 22 CDDO or CDDO biotin were first reacted with SA-sepharose, and then combined with purified Lon.…”

Section: Cddo Interacts Directly With Purified and Cellular Lonmentioning

confidence: 99%

“…[24][25][26][27][28] We show that Lon is substantially upregulated in human malignant B-cell lymphoma patient samples and cell lines compared with resting or activated normal donor peripheral blood B cells. We also show that CDDO and its derivatives directly and selectively inhibit Lon-mediated proteolysis.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

Bernstein

Venkatesh

et al. 2012

Blood

128

125

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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. IntroductionThe malignant transformation of normal cells into cancer cells is driven principally by enhanced oncogenic protein function and/or inactivation of tumor suppressors. To promote this transformation process, tumor cells undergo an extensive reprogramming of normal growth and survival pathways that are mediated by nononcogenic proteins. The identification of nononcogenic proteins that are essential for the survival and proliferation of cancer cells provides potential new drug targets for anticancer therapeutics. Nononcogenic proteins participating in the cell stress response have emerged as a unique and important class of viable targets. Recent work demonstrates that pharmacologic inhibition or downregulation of the master transcriptional regulator of the cell stress response-heat shock factor 1 (HSF1), 1 as well as of the molecular chaperones HSP70 or HSP90, selectively inhibit tumor development. 2,3 Remarkably, the inhibition or down-regulation of these essential heat-shock response proteins effectively limits cancer cell growth without substantially compromising normal cell survival. 1,2,4 Luo and colleagues 6 have expanded on the classic hallmarks of cancer originally proposed by Hanahan and Weinberg 5 to include several common stress phenotypes of tumorigenesis. The neoplastic transformation of cancer cells gives rise to diverse oncogenic stressors such as DNA damage and mitotic stress, as well as to metabolic, proteotoxic, and oxidative stress. Cancer cells thus depend on conserved defense mechanisms to survive such oncogenic str...

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2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis

Cited by 17 publications

References 43 publications

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β

The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-κB activation through direct inhibition of IκB kinase β

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives

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