TY - JOUR
T1 - A novel mechanism of action of methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate
T2 - Direct permeabilization of the inner mitochondrial membrane to inhibit electron transport and induce apoptosis
AU - Samudio, Ismael
AU - Konopleva, Marina
AU - Pelicano, Helene
AU - Huang, Peng
AU - Frolova, Olga
AU - Bornmann, William
AU - Ying, Yunming
AU - Evans, Randall
AU - Contractor, Rooha
AU - Andreeff, Michael
PY - 2006/4
Y1 - 2006/4
N2 - Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me) is a synthetic oleanolic acid derivative that displays antitumorigenic and anti-inflammatory activities, and we have previously reported that this agent potently activates the intrinsic apoptotic pathway in leukemia cells. In this study, we demonstrate that mitochondrial dysfunction induced by CDDO-Me is mediated by direct permeabilization of the inner mitochondrial membrane, which results in the rapid depletion of mitochondrial glutathione (GSXm), loss of cardiolipin, and inhibition of mitochondrial respiration. More importantly, we demonstrate that in addition to activating the intrinsic apoptotic pathway, the mitochondrial effects of CDDO-Me may mediate its anti-inflammatory activity by modulating the generation of superoxide anion (O2.-). It is noteworthy that CDDO-Me did not increase the generation of O2.-, and pretreatment of leukemia cells with CDDO-Me prevented the increase of this reactive oxygen species elicited by inhibition of complex I or III in the absence of de novo protein synthesis. CDDO-Me, but not other inhibitors of respiration, induced a time- and dose-dependent, cyclosporin A-independent permeability transition (PT) of isolated mitochondria that was sensitive to sulfhydryl antioxidants but not to EDTA. PT induced by CDDO-Me and Ca 2+ was accompanied by loss of GSXm, suggesting that the increased permeability of the inner mitochondrial membrane facilitates the loss of this antioxidant. Finally, transmission electron microscopy revealed that CDDO-Me rapidly induced caspase-independent mitochondrial swelling and loss of inner membrane structure before the release of cytochrome c. Taken together, our results indicate that CDDO-Me is a novel mitochondriotoxic agent that induces apoptosis and inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity.
AB - Methyl-2-cyano-3,12 dioxoolean-1,9 diene-28-oate (CDDO-Me) is a synthetic oleanolic acid derivative that displays antitumorigenic and anti-inflammatory activities, and we have previously reported that this agent potently activates the intrinsic apoptotic pathway in leukemia cells. In this study, we demonstrate that mitochondrial dysfunction induced by CDDO-Me is mediated by direct permeabilization of the inner mitochondrial membrane, which results in the rapid depletion of mitochondrial glutathione (GSXm), loss of cardiolipin, and inhibition of mitochondrial respiration. More importantly, we demonstrate that in addition to activating the intrinsic apoptotic pathway, the mitochondrial effects of CDDO-Me may mediate its anti-inflammatory activity by modulating the generation of superoxide anion (O2.-). It is noteworthy that CDDO-Me did not increase the generation of O2.-, and pretreatment of leukemia cells with CDDO-Me prevented the increase of this reactive oxygen species elicited by inhibition of complex I or III in the absence of de novo protein synthesis. CDDO-Me, but not other inhibitors of respiration, induced a time- and dose-dependent, cyclosporin A-independent permeability transition (PT) of isolated mitochondria that was sensitive to sulfhydryl antioxidants but not to EDTA. PT induced by CDDO-Me and Ca 2+ was accompanied by loss of GSXm, suggesting that the increased permeability of the inner mitochondrial membrane facilitates the loss of this antioxidant. Finally, transmission electron microscopy revealed that CDDO-Me rapidly induced caspase-independent mitochondrial swelling and loss of inner membrane structure before the release of cytochrome c. Taken together, our results indicate that CDDO-Me is a novel mitochondriotoxic agent that induces apoptosis and inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity.
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U2 - 10.1124/mol.105.018051
DO - 10.1124/mol.105.018051
M3 - Article
C2 - 16410408
AN - SCOPUS:33645108498
SN - 0026-895X
VL - 69
SP - 1182
EP - 1193
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 4
ER -