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Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: A new strategy in anti-apoptotic drug discovery

Kagan, VE and Bayir, A and Bayir, H and Stoyanovsky, D and Borisenko, GG and Tyurina, YY and Wipf, P and Atkinson, J and Greenberger, JS and Chapkin, RS and Belikova, NA (2009) Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: A new strategy in anti-apoptotic drug discovery. Molecular Nutrition and Food Research, 53 (1). 104 - 114. ISSN 1613-4125

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There critical role of mitochondria in programmed cell death leads to the design of mitochondriotropic agents as a strategy in regulating apoptosis. For anticancer therapy, stimulation of proapoptotic mito-chondrial events in tumor cells and their suppression in surrounding normal cells represents a promising paradigm for new therapies. Different approaches targeting regulation of components of mito-chondrial antioxidant system such as Mn-SOD demonstrated significant antitumor efficiency, particularly in combination therapy. This review is focused on a newly discovered early stage of mitochondria-dependent apoptosis -oxidative lipid signaling involving a mitochondria-specific phospholipid cardiolipin (CL). Cytochrome c (cyt c) acts as a CL-specific peroxidase very early in apoptosis. At this stage, the hostile events are still secluded within the mitochondria and do not reach the cytosolic targets. CL oxidation process is required for the release of pro-apoptotic factors into the cytosol. Manipulation of cyt c interactions with CL, inhibition of peroxidase activity, and prevention of CL peroxidation are prime targets for the discovery of anti-apoptotic drugs acting before the "point-of-no-return" in the fulfillment of the cell death program. Therefore, mitochondria-targeted disruptors and inhibitors of cyt c/CL peroxidase complexes and suppression of CL peroxidation represent new strategies in anti-apoptotic drug discovery., © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Kagan, VEkagan@pitt.eduKAGAN
Bayir, A
Bayir, Hhub22@pitt.eduHUB220000-0003-2361-4120
Stoyanovsky, Ddas11@pitt.eduDAS110000-0001-5591-4780
Borisenko, GG
Tyurina, YYyyt1@pitt.eduYYT1
Wipf, Ppwipf@pitt.eduPWIPF
Atkinson, J
Greenberger, JSjoelg@pitt.eduJOELG
Chapkin, RS
Belikova, NA
Date: 1 January 2009
Date Type: Publication
Journal or Publication Title: Molecular Nutrition and Food Research
Volume: 53
Number: 1
Page Range: 104 - 114
DOI or Unique Handle: 10.1002/mnfr.200700402
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1613-4125
Article Type: Review
MeSH Headings: Amino Acid Sequence; Animals; Antineoplastic Agents--pharmacology; Antineoplastic Agents--therapeutic use; Antioxidants--therapeutic use; Apoptosis--drug effects; Autophagy--drug effects; Cardiolipins--pharmacology; Cardiolipins--physiology; Cardiolipins--therapeutic use; Conserved Sequence; Cytochromes c--antagonists & inhibitors; Cytochromes c--chemistry; Enzyme Inhibitors--pharmacology; Enzyme Inhibitors--therapeutic use; Humans; Mitochondria--drug effects; Mitochondria--physiology; Models, Molecular; Molecular Sequence Data; Neoplasms--drug therapy; Protein Conformation; Sequence Alignment
Other ID: NLM NIHMS94427, NLM PMC2659540
PubMed Central ID: PMC2659540
PubMed ID: 18979502
Date Deposited: 03 Jul 2013 14:57
Last Modified: 19 Aug 2020 20:55


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