Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: a new strategy in anti-apoptotic drug discovery.
The 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.
Kagan
Valerian E
VE
Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA. kagan@pitt.edu
Bayir
Ayse
A
Bayir
Hulya
H
Stoyanovsky
Detcho
D
Borisenko
Grigory G
GG
Tyurina
Yulia Y
YY
Wipf
Peter
P
Atkinson
Jeffrey
J
Greenberger
Joel S
JS
Chapkin
Robert S
RS
Belikova
Natalia A
NA
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002308:Cardiolipins / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D017124:Conserved Sequence; D045304:Cytochromes c / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D016415:Sequence Alignment
D000970:Antineoplastic Agents; D000975:Antioxidants; D002308:Cardiolipins; D004791:Enzyme Inhibitors; D045304:Cytochromes c