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Molecular Pharmacology

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Research ArticleOriginal Article

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

Ismael Samudio, Marina Konopleva, Helene Pelicano, Peng Huang, Olga Frolova, William Bornmann, Yunming Ying, Randall Evans, Rooha Contractor and Michael Andreeff
Molecular Pharmacology April 2006, 69 (4) 1182-1193; DOI: https://doi.org/10.1124/mol.105.018051
Ismael Samudio
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Marina Konopleva
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Helene Pelicano
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Peng Huang
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Olga Frolova
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William Bornmann
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Yunming Ying
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Randall Evans
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Rooha Contractor
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Michael Andreeff
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Abstract

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 (Math). It is noteworthy that CDDO-Me did not increase the generation of Math, 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 Ca2+ 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.

  • Received August 15, 2005.
  • Accepted January 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (4)
Molecular Pharmacology
Vol. 69, Issue 4
1 Apr 2006
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Research ArticleOriginal Article

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

Ismael Samudio, Marina Konopleva, Helene Pelicano, Peng Huang, Olga Frolova, William Bornmann, Yunming Ying, Randall Evans, Rooha Contractor and Michael Andreeff
Molecular Pharmacology April 1, 2006, 69 (4) 1182-1193; DOI: https://doi.org/10.1124/mol.105.018051

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Research ArticleOriginal Article

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

Ismael Samudio, Marina Konopleva, Helene Pelicano, Peng Huang, Olga Frolova, William Bornmann, Yunming Ying, Randall Evans, Rooha Contractor and Michael Andreeff
Molecular Pharmacology April 1, 2006, 69 (4) 1182-1193; DOI: https://doi.org/10.1124/mol.105.018051
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