The novel triterpenoid CDDO and its derivatives induce apoptosis by disruption of intracellular redox balance.
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 NH(2)-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 NH(2)-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.
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology; D020298:U937 Cells; D014764:Viral Proteins
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000975:Antioxidants; D003574:Cytochrome c Group; D016877:Oxidants; D017382:Reactive Oxygen Species; D015843:Serpins; D014764:Viral Proteins; D009828:Oleanolic Acid; C074641:interleukin-1beta-converting enzyme inhibitor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D005978:Glutathione