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Mitochondria‐targeted disruptors and inhibitors of cytochrome c /cardiolipin peroxidase complexes: A new strategy in anti‐apoptotic drug discovery
Author(s) -
Kagan Valerian E.,
Bayir Ayse,
Bayir Hulya,
Stoyanovsky Detcho,
Borisenko Grigory G.,
Tyurina Yulia Y.,
Wipf Peter,
Atkinson Jeffrey,
Greenberger Joel S.,
Chapkin Robert S.,
Belikova Natalia A.
Publication year - 2009
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.200700402
Subject(s) - cardiolipin , mitochondrion , cytochrome c , apoptosis , programmed cell death , lipid peroxidation , cytosol , microbiology and biotechnology , peroxidase , biochemistry , chemistry , phospholipid hydroperoxide glutathione peroxidase , biology , pharmacology , antioxidant , glutathione peroxidase , phospholipid , enzyme , superoxide dismutase , membrane
Thre 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 mitochondrial 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 mitochondrial 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.