Mitochondria-targeted disruptors and inhibitors of cytochrome c/cardiolipin peroxidase complexes: a new strategy in anti-apoptotic drug discovery.
Kagan-VE; Bayin-A; Bayin-H; Stoyanovsky-D; Borisenko-GG; Tyurina-YY; Wipf-P; Atkinson-J; Greenberger-JS; Chapkin-RS; Belikova-NA
Mol Nutr Food Res 2009 Jan; 53(1):104-114
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.
Cell-damage; Cell-biology; Cell-metabolism; Cellular-reactions; Cellular-uptake; Cancer; Bacterial-cultures; Biochemical-analysis; Biochemistry; Biological-agents; Biological-effects; Immune-reaction;
Author Keywords: Apoptosis; Cardiolipin; Cytochrome c; Drug delivery; Mitochondria-targeting
Dr. Valerian E. Kagan, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, PA 15219-3130
Molecular Nutrition & Food Research
University of Pittsburgh at Pittsburgh