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[Cancer Research 63, 5551-5558, September 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

The Novel Triterpenoid CDDO and its Derivatives Induce Apoptosis by Disruption of Intracellular Redox Balance1

Takashi Ikeda, Michael Sporn, Tadashi Honda, Gordon W. Gribble and Donald Kufe2

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

The novel oleanane triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) induces apoptosis of human leukemia cells by activation of the extrinsic caspase-8 pathway. The mechanisms responsible for the proapoptotic effects of CDDO are unknown. The present studies demonstrate that CDDO activates the c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in U-937 leukemia cells. The results also show that CDDO activates stress kinases by increasing levels of reactive oxygen species and decreasing intracellular glutathione (GSH) concentrations. Similar findings were obtained with the C-28 methyl ester (CDDO-Me) and C-28 imidazolide ester (CDDO-Im) derivatives. The results also demonstrate that CDDO-induced: (a) stimulation of Jun NH2-terminal kinase; (b) activation of caspase-8; (c) loss of mitochondrial transmembrane potential; (d) release of cytochrome c; and (e) cleavage of caspase-3 are blocked by pretreatment with the antioxidant N-acetyl-L-cysteine and GSH but not with cysteine. In concert with these results, CDDO-induced apoptosis is also abrogated by N-acetyl-L-cysteine and GSH. These findings demonstrate that CDDO and its derivatives disrupt intracellular redox balance and thereby induce apoptosis.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2003 by the American Association for Cancer Research.