Cancer Research Audrey Hepburn Sign up for Cancer Research eTOC's
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
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 Email this article to a friend
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 reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Konopleva, M.
Right arrow Articles by Andreeff, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Konopleva, M.
Right arrow Articles by Andreeff, M.
[Cancer Research 64, 7927-7935, November 1, 2004]
© 2004 American Association for Cancer Research

Regular Articles

The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Caspase-Dependent and -Independent Apoptosis in Acute Myelogenous Leukemia

Marina Konopleva1, Twee Tsao1, Zeev Estrov2, Ruey-min Lee5, Rui-Yu Wang1, C. Ellen Jackson1, Teresa McQueen1, Giuseppe Monaco6, Mark Munsell3, John Belmont6, Hagop Kantarjian4, Michael B. Sporn7 and Michael Andreeff1,4

1 Section of Molecular Hematology and Therapy and the Departments of Blood and Marrow Transplantation, 2 Bioimmunotherapy, 3 Biostatistics, and 4 Leukemia at The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 5 Huntsman Cancer Institute at University of Utah, Salt Lake City, Utah; 6 Baylor College of Medicine, Houston, Texas; and 7 Dartmouth Medical School, Hanover, New Hampshire

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
R. Vene, P. Larghero, G. Arena, M. B. Sporn, A. Albini, and F. Tosetti
Glycogen Synthase Kinase 3{beta} Regulates Cell Death Induced by Synthetic Triterpenoids
Cancer Res., September 1, 2008; 68(17): 6987 - 6996.
[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
 JNCI J Natl Cancer InstHome page
W. Zhang, M. Konopleva, Y.-x. Shi, T. McQueen, D. Harris, X. Ling, Z. Estrov, A. Quintas-Cardama, D. Small, J. Cortes, et al.
Mutant FLT3: A Direct Target of Sorafenib in Acute Myelogenous Leukemia
J Natl Cancer Inst, February 6, 2008; 100(3): 184 - 198.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
S. Papineni, S. Chintharlapalli, and S. Safe
Methyl 2-Cyano-3,11-dioxo-18{beta}-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells
Mol. Pharmacol., February 1, 2008; 73(2): 553 - 565.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. York, M. Abdelrahim, S. Chintharlapalli, S. D. Lucero, and S. Safe
1,1-Bis(3'-Indolyl)-1-(p-Substitutedphenyl)methanes Induce Apoptosis and Inhibit Renal Cell Carcinoma Growth
Clin. Cancer Res., November 15, 2007; 13(22): 6743 - 6752.
[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
 Cancer Res.Home page
S. Chintharlapalli, S. Papineni, S. K. Ramaiah, and S. Safe
Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors
Cancer Res., March 15, 2007; 67(6): 2816 - 2823.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Milella, M. Konopleva, C. M. Precupanu, Y. Tabe, M. R. Ricciardi, C. Gregorj, S. J. Collins, B. Z. Carter, C. D'Angelo, M. T. Petrucci, et al.
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis
Blood, March 1, 2007; 109(5): 2121 - 2129.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
P. S. Brookes, K. Morse, D. Ray, A. Tompkins, S. M. Young, S. Hilchey, S. Salim, M. Konopleva, M. Andreeff, R. Phipps, et al.
The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid and Its Derivatives Elicit Human Lymphoid Cell Apoptosis through a Novel Pathway Involving the Unregulated Mitochondrial Permeability Transition Pore
Cancer Res., February 15, 2007; 67(4): 1793 - 1802.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
U. Testa and R. Riccioni
Deregulation of apoptosis in acute myeloid leukemia
Haematologica, January 1, 2007; 92(1): 81 - 94.
[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
 Molecular Cancer TherapeuticsHome page
M. M. Yore, K. T. Liby, T. Honda, G. W. Gribble, and M. B. Sporn
The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-{kappa}B activation through direct inhibition of I{kappa}B kinase {beta}
Mol. Cancer Ther., December 1, 2006; 5(12): 3232 - 3239.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home 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
 Int ImmunolHome page
N. Intasai, S. Mai, W. Kasinrerk, and C. Tayapiwatana
Binding of multivalent CD147 phage induces apoptosis of U937 cells
Int. Immunol., July 1, 2006; 18(7): 1159 - 1169.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
Y. Ji, H. J. Lee, C. Goodman, M. Uskokovic, K. Liby, M. Sporn, and N. Suh
The synthetic triterpenoid CDDO-imidazolide induces monocytic differentiation by activating the Smad and ERK signaling pathways in HL60 leukemia cells.
Mol. Cancer Ther., June 1, 2006; 5(6): 1452 - 1458.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
I. Samudio, M. Konopleva, H. Pelicano, P. Huang, O. Frolova, W. Bornmann, Y. Ying, R. Evans, R. Contractor, and M. Andreeff
A Novel Mechanism of Action of Methyl-2-cyano-3,12 Dioxoolean-1,9 Diene-28-oate: Direct Permeabilization of the Inner Mitochondrial Membrane to Inhibit Electron Transport and Induce Apoptosis
Mol. Pharmacol., April 1, 2006; 69(4): 1182 - 1193.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. S. Yates, M.-K. Kwak, P. A. Egner, J. D. Groopman, S. Bodreddigari, T. R. Sutter, K. J. Baumgartner, B.D. Roebuck, K. T. Liby, M. M. Yore, et al.
Potent Protection against Aflatoxin-Induced Tumorigenesis through Induction of Nrf2-Regulated Pathways by the Triterpenoid 1-[2-Cyano-3-,12-Dioxooleana-1,9(11)-Dien-28-Oyl]Imidazole
Cancer Res., February 15, 2006; 66(4): 2488 - 2494.
[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
 Molecular Cancer TherapeuticsHome page
I. Samudio, M. Konopleva, S. Safe, T. McQueen, and M. Andreeff
Guggulsterones induce apoptosis and differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the pregnadienedione structure
Mol. Cancer Ther., December 1, 2005; 4(12): 1982 - 1992.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home 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
 Molecular Cancer TherapeuticsHome page
C.-C. Wu, M.-L. Chan, W.-Y. Chen, C.-Y. Tsai, F.-R. Chang, and Y.-C. Wu
Pristimerin induces caspase-dependent apoptosis in MDA-MB-231 cells via direct effects on mitochondria
Mol. Cancer Ther., August 1, 2005; 4(8): 1277 - 1285.
[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 HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2004 by the American Association for Cancer Research.