Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, α-tocopherol succinate (α-TOS) and α-tocopherol phosphate (α-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that α-TOS and α-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with α-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by α-TOS may contribute to its known anti-cancer pharmacological activity.

• Klíčová slova
• Cancer Therapy, Computer Modeling, Cytochrome c, Peroxidase, Protein Folding, Vitamin E,
• MeSH
• aktivace enzymů účinky léků   MeSH
• alfa-tokoferol analogy a deriváty   chemie   farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčné linie MeSH
• cytochromy c chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koně MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• peroxidasa chemie   metabolismus   MeSH
• spektrofotometrie MeSH
• terciární struktura proteinů MeSH
• vazba proteinů MeSH
• vazebná místa genetika   MeSH
• vitaminy chemie   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• alfa-tokoferol MeSH
• alpha-tocopherol phosphate MeSH Prohlížeč
• cytochromy c MeSH
• peroxidasa MeSH
• vitaminy MeSH

Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic field, respectively, and shifted and rebuilt frequency spectra. Disturbed electrodynamic interaction forces between cancer and healthy cells may favor local invasion and metastasis. A therapeutic strategy of targeting dysfunctional mitochondria for restoration of their physiological functions makes it possible to switch on the natural apoptotic pathway blocked in cancer transformed cells. Experience with dichloroacetate in cancer treatment and reestablishment of the healthy state may help in the development of novel effective drugs aimed at the mitochondrial function.

• MeSH
• biologické modely * MeSH
• elektromagnetická pole * MeSH
• lidé MeSH
• mitochondrie účinky záření   MeSH
• nádorová transformace buněk účinky záření   MeSH
• nádory patofyziologie   MeSH
• přenos energie * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of α-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. RESULTS: MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorter-chain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. INNOVATION AND CONCLUSION: We conclude that MitoVES, a mitochondrially targeted analog of α-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing.

• MeSH
• alfa-tokoferol analogy a deriváty   farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• endoteliální buňky účinky léků   MeSH
• hojení ran účinky léků   MeSH
• inhibitory angiogeneze chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondrie účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• nádory krevní zásobení   farmakoterapie   MeSH
• patologická angiogeneze farmakoterapie   MeSH
• proliferace buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• alfa-tokoferol MeSH
• inhibitory angiogeneze MeSH
• mitochondriální DNA MeSH