CG&D
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ito, Y.
Right arrow Articles by Kufe, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ito, Y.
Right arrow Articles by Kufe, D.
Cell Growth & Differentiation Vol. 11, 261-267, May 2000
© 2000 American Association for Cancer Research


Articles

The Novel Triterpenoid 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid Induces Apoptosis of Human Myeloid Leukemia Cells by a Caspase-8-dependent Mechanism1

Yasumasa Ito, Pramod Pandey, Andrew Place, Michael B. Sporn, Gordon W. Gribble, Tadashi Honda, Surender Kharbanda and Donald Kufe2

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [Y. I., P. P., S. K., D. K.], and Norris Cotton Cancer Center and Department of Pharmacology, Dartmouth Medical School [A. P., M. B. S.], Department of Chemistry, Dartmouth College [G. W. G., T. H.], Hanover, New Hampshire 03755

Abstract

The oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a multifunctional molecule that induces growth inhibition and differentiation of human myeloid leukemia cells. The present studies demonstrate that CDDO treatment results in apoptosis of U-937 and HL-60 myeloid leukemia cells. Similar to 1-ß-D-arabinofuranosylcytosine (ara-C), another agent that inhibits growth and induces apoptosis of these cells, CDDO induced the release of mitochondrial cytochrome c and activation of caspase-3. Overexpression of Bcl-xL blocked cytochrome c release, caspase-3 activation, and apoptosis in ara-C-treated cells. By contrast, CDDO-induced release of cytochrome c, and activation of caspase-3 were diminished only in part by Bcl-xL. In concert with these findings, we demonstrate that CDDO, but not ara-C, activates caspase-8 and thereby caspase-3 by a cytochrome c-independent mechanism. The results also show that CDDO-induced cytochrome c release is mediated by caspase-8-dependent cleavage of Bid. These findings demonstrate that CDDO induces apoptosis of myeloid leukemia cells and that this novel agent activates an apoptotic signaling cascade distinct from that induced by the cytotoxic agent ara-C.




This article has been cited by other articles:


Home page
Mol. Pharmacol.Home page
U.-H. Jin, Y. Cheng, B. Zhou, and S. Safe
Bardoxolone Methyl and a Related Triterpenoid Downregulate cMyc Expression in Leukemia Cells
Mol. Pharmacol., May 1, 2017; 91(5): 438 - 450.
[Abstract] [Full Text] [PDF]


Home page
Pharmacol. Rev.Home page
K. T. Liby and M. B. Sporn
Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease
Pharmacol. Rev., September 28, 2012; 64(4): 972 - 1003.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
C. To, B. H. Shilton, and G. M. Di Guglielmo
Synthetic Triterpenoids Target the Arp2/3 Complex and Inhibit Branched Actin Polymerization
J. Biol. Chem., September 3, 2010; 285(36): 27944 - 27957.
[Abstract] [Full Text] [PDF]


Home page
Mol Cancer ResHome page
R. Ahmad, S. Liu, E. Weisberg, E. Nelson, I. Galinsky, C. Meyer, D. Kufe, S. Kharbanda, and R. Stone
Combining the FLT3 Inhibitor PKC412 and the Triterpenoid CDDO-Me Synergistically Induces Apoptosis in Acute Myeloid Leukemia with the Internal Tandem Duplication Mutation
Mol. Cancer Res., July 1, 2010; 8(7): 986 - 993.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
T. Tsao, S. Kornblau, S. Safe, J. C. Watt, V. Ruvolo, W. Chen, Y. Qiu, K. R. Coombes, Z. Ju, M. Abdelrahim, et al.
Role of Peroxisome Proliferator-Activated Receptor-{gamma} and Its Coactivator DRIP205 in Cellular Responses to CDDO (RTA-401) in Acute Myelogenous Leukemia
Cancer Res., June 15, 2010; 70(12): 4949 - 4960.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
B. Daroczi, G. Kari, Q. Ren, A. P. Dicker, and U. Rodeck
Nuclear factor {kappa}B inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos
Mol. Cancer Ther., September 1, 2009; 8(9): 2625 - 2634.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
I. Samudio, S. Kurinna, P. Ruvolo, B. Korchin, H. Kantarjian, M. Beran, K. Dunner Jr., S. Kondo, M. Andreeff, and M. Konopleva
Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells
Mol. Cancer Ther., May 1, 2008; 7(5): 1130 - 1139.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
R. Ahmad, D. Raina, C. Meyer, and D. Kufe
Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)->Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3
Cancer Res., April 15, 2008; 68(8): 2920 - 2926.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
M. L. Hyer, R. Shi, M. Krajewska, C. Meyer, I. V. Lebedeva, P. B. Fisher, and J. C. Reed
Apoptotic Activity and Mechanism of 2-Cyano-3,12-Dioxoolean-1,9-Dien-28-Oic-Acid and Related Synthetic Triterpenoids in Prostate Cancer
Cancer Res., April 15, 2008; 68(8): 2927 - 2933.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
S. Koschmieder, F. D'Alo, H. Radomska, C. Schoneich, J. S. Chang, M. Konopleva, S. Kobayashi, E. Levantini, N. Suh, A. Di Ruscio, et al.
CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer binding protein alpha
Blood, November 15, 2007; 110(10): 3695 - 3705.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
K. Liby, T. Honda, C. R. Williams, R. Risingsong, D. B. Royce, N. Suh, A. T. Dinkova-Kostova, K. K. Stephenson, P. Talalay, C. Sundararajan, et al.
Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities
Mol. Cancer Ther., July 1, 2007; 6(7): 2113 - 2119.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
K. Liby, D. B. Royce, C. R. Williams, R. Risingsong, M. M. Yore, T. Honda, G. W. Gribble, E. Dmitrovsky, T. A. Sporn, and M. B. Sporn
The Synthetic Triterpenoids CDDO-Methyl Ester and CDDO-Ethyl Amide Prevent Lung Cancer Induced by Vinyl Carbamate in A/J Mice
Cancer Res., March 15, 2007; 67(6): 2414 - 2419.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
M. S. Yates, M. Tauchi, F. Katsuoka, K. C. Flanders, K. T. Liby, T. Honda, G. W. Gribble, D. A. Johnson, J. A. Johnson, N. C. Burton, et al.
Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes
Mol. Cancer Ther., January 1, 2007; 6(1): 154 - 162.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
R. Ahmad, D. Raina, C. Meyer, S. Kharbanda, and D. Kufe
Triterpenoid CDDO-Me Blocks the NF-{kappa}B Pathway by Direct Inhibition of IKKbeta on Cys-179
J. Biol. Chem., November 24, 2006; 281(47): 35764 - 35769.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
P. Lei, M. Abdelrahim, and S. Safe
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways.
Mol. Cancer Ther., September 1, 2006; 5(9): 2324 - 2336.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
R. D. Couch, N. J. Ganem, M. Zhou, V. M. Popov, T. Honda, T. D. Veenstra, M. B. Sporn, and A. C. Anderson
2-Cyano-3,12-dioxooleana-1,9(11)-diene-28-oic Acid Disrupts Microtubule Polymerization: A Possible Mechanism Contributing to Apoptosis
Mol. Pharmacol., April 1, 2006; 69(4): 1158 - 1165.
[Abstract] [Full Text] [PDF]


Home page
The OncologistHome page
M. S. Ricci and W.-X. Zong
Chemotherapeutic approaches for targeting cell death pathways.
Oncologist, April 1, 2006; 11(4): 342 - 357.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
M. Konopleva, W. Zhang, Y.-X. Shi, T. McQueen, T. Tsao, M. Abdelrahim, M. F. Munsell, M. Johansen, D. Yu, T. Madden, et al.
Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells.
Mol. Cancer Ther., February 1, 2006; 5(2): 317 - 328.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
I. Samudio, M. Konopleva, N. Hail Jr., Y.-X. Shi, T. McQueen, T. Hsu, R. Evans, T. Honda, G. W. Gribble, M. Sporn, et al.
2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) Directly Targets Mitochondrial Glutathione to Induce Apoptosis in Pancreatic Cancer
J. Biol. Chem., October 28, 2005; 280(43): 36273 - 36282.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
J. C. Reed and M. Pellecchia
Apoptosis-based therapies for hematologic malignancies
Blood, July 15, 2005; 106(2): 408 - 418.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
S. Chintharlapalli, S. Papineni, M. Konopleva, M. Andreef, I. Samudio, and S. Safe
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 {gamma}-Dependent and -Independent Pathways
Mol. Pharmacol., July 1, 2005; 68(1): 119 - 128.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
K. Liby, T. Hock, M. M. Yore, N. Suh, A. E. Place, R. Risingsong, C. R. Williams, D. B. Royce, T. Honda, Y. Honda, et al.
The Synthetic Triterpenoids, CDDO and CDDO-Imidazolide, Are Potent Inducers of Heme Oxygenase-1 and Nrf2/ARE Signaling
Cancer Res., June 1, 2005; 65(11): 4789 - 4798.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
M. Konopleva, T. Tsao, Z. Estrov, R.-m. Lee, R.-Y. Wang, C. E. Jackson, T. McQueen, G. Monaco, M. Munsell, J. Belmont, et al.
The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Caspase-Dependent and -Independent Apoptosis in Acute Myelogenous Leukemia
Cancer Res., November 1, 2004; 64(21): 7927 - 7935.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
W. Zou, X. Liu, P. Yue, Z. Zhou, M. B. Sporn, R. Lotan, F. R. Khuri, and S.-Y. Sun
c-Jun NH2-Terminal Kinase-Mediated Up-regulation of Death Receptor 5 Contributes to Induction of Apoptosis by the Novel Synthetic Triterpenoid Methyl-2-Cyano-3,12-Dioxooleana-1, 9-Dien-28-Oate in Human Lung Cancer Cells
Cancer Res., October 15, 2004; 64(20): 7570 - 7578.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
P. A. Svingen, D. Loegering, J. Rodriquez, X. W. Meng, P. W. Mesner Jr., S. Holbeck, A. Monks, S. Krajewski, D. A. Scudiero, E. A. Sausville, et al.
Components of the Cell Death Machine and Drug Sensitivity of the National Cancer Institute Cell Line Panel
Clin. Cancer Res., October 15, 2004; 10(20): 6807 - 6820.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
N. Hail Jr., M. Konopleva, M. Sporn, R. Lotan, and M. Andreeff
Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)
J. Biol. Chem., March 19, 2004; 279(12): 11179 - 11187.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
T. Ikeda, Y. Nakata, F. Kimura, K. Sato, K. Anderson, K. Motoyoshi, M. Sporn, and D. 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
Mol. Cancer Ther., January 1, 2004; 3(1): 39 - 45.
[Abstract] [Full Text]


Home page
Mol. Pharmacol.Home page
K. R. Kalli, K. E. Devine, M. C. Cabot, C. R. Arnt, M. P. Heldebrant, P. A. Svingen, C. Erlichman, L. C. Hartmann, C. A. Conover, and S. H. Kaufmann
Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines
Mol. Pharmacol., December 1, 2003; 64(6): 1434 - 1443.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
T. Ikeda, M. Sporn, T. Honda, G. W. Gribble, and D. Kufe
The Novel Triterpenoid CDDO and its Derivatives Induce Apoptosis by Disruption of Intracellular Redox Balance
Cancer Res., September 1, 2003; 63(17): 5551 - 5558.
[Abstract] [Full Text] [PDF]


Home page
Clin. Cancer Res.Home page
A. E. Place, N. Suh, C. R. Williams, R. Risingsong, T. Honda, Y. Honda, G. W. Gribble, L. M. Leesnitzer, J. B. Stimmel, T. M. Willson, et al.
The Novel Synthetic Triterpenoid, CDDO-Imidazolide, Inhibits Inflammatory Response and Tumor Growth in Vivo
Clin. Cancer Res., July 1, 2003; 9(7): 2798 - 2806.
[Abstract] [Full Text] [PDF]


Home page
Cancer Res.Home page
N. Suh, A. B. Roberts, S. Birkey Reffey, K. Miyazono, S. Itoh, P. t. Dijke, E. H. Heiss, A. E. Place, R. Risingsong, C. R. Williams, et al.
Synthetic Triterpenoids Enhance Transforming Growth Factor {beta}/Smad Signaling
Cancer Res., March 15, 2003; 63(6): 1371 - 1376.
[Abstract] [Full Text] [PDF]


Home page
ASH Education BookHome page
W. L. Carroll, D. Bhojwani, D.-J. Min, E. Raetz, M. Relling, S. Davies, J. R. Downing, C. L. Willman, and J. C. Reed
Pediatric Acute Lymphoblastic Leukemia
Hematology, January 1, 2003; 2003(1): 102 - 131.
[Abstract] [Full Text] [PDF]


Home page
J. Lipid Res.Home page
C. E. Clay, A. Monjazeb, J. Thorburn, F. H. Chilton, and K. P. High
15-Deoxy-{Delta}12,14-prostaglandin J2-induced apoptosis does not require PPAR{gamma} in breast cancer cells
J. Lipid Res., November 1, 2002; 43(11): 1818 - 1828.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
I. M. Pedersen, S. Kitada, A. Schimmer, Y. Kim, J. M. Zapata, L. Charboneau, L. Rassenti, M. Andreeff, F. Bennett, M. B. Sporn, et al.
The triterpenoid CDDO induces apoptosis in refractory CLL B cells
Blood, September 26, 2002; 100(8): 2965 - 2972.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
Y. Kim, N. Suh, M. Sporn, and J. C. Reed
An Inducible Pathway for Degradation of FLIP Protein Sensitizes Tumor Cells to TRAIL-induced Apoptosis
J. Biol. Chem., June 21, 2002; 277(25): 22320 - 22329.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
T. A. Stadheim, N. Suh, N. Ganju, M. B. Sporn, and A. Eastman
The Novel Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) Potently Enhances Apoptosis Induced by Tumor Necrosis Factor in Human Leukemia Cells
J. Biol. Chem., May 10, 2002; 277(19): 16448 - 16455.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
P. Chu, D. Deforce, I. M. Pedersen, Y. Kim, S. Kitada, J. C. Reed, and T. J. Kipps
Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia
PNAS, March 19, 2002; 99(6): 3854 - 3859.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
K. B. Kim, R. Lotan, P. Yue, M. B. Sporn, N. Suh, G. W. Gribble, T. Honda, G. S. Wu, W. K. Hong, and S.-Y. Sun
Identification of a Novel Synthetic Triterpenoid, Methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, That Potently Induces Caspase-mediated Apoptosis in Human Lung Cancer Cells
Mol. Cancer Ther., January 1, 2002; 1(3): 177 - 184.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
M. Konopleva, T. Tsao, P. Ruvolo, I. Stiouf, Z. Estrov, C. E. Leysath, S. Zhao, D. Harris, S. Chang, C. E. Jackson, et al.
Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia
Blood, January 1, 2002; 99(1): 326 - 335.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
A. D. Schimmer, D. W. Hedley, L. Z. Penn, and M. D. Minden
Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view
Blood, December 15, 2001; 98(13): 3541 - 3553.
[Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
Y. Ito, P. Pandey, M. B. Sporn, R. Datta, S. Kharbanda, and D. Kufe
The Novel Triterpenoid CDDO Induces Apoptosis and Differentiation of Human Osteosarcoma Cells by a Caspase-8 Dependent Mechanism
Mol. Pharmacol., May 1, 2001; 59(5): 1094 - 1099.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2000 by the American Association of Cancer Research.