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[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.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
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Copyright © 2004 by the American Association for Cancer Research.