Document Detail


Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue.
MedLine Citation:
PMID:  22627082     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The effects of α-tocopheryl succinate (α-TOS), α-tocopheryl acetyl ether (α-TEA) and triphenylphosphonium-tagged vitamin E succinate (mitochondrially targeted vitamin E succinate; MitoVES) on energy-related mitochondrial functions were determined in mitochondria isolated from AS-30D hepatoma and rat liver, bovine heart sub-mitochondrial particles (SMPs), and in rodent and human carcinoma cell lines and rat hepatocytes. In isolated mitochondria, MitoVES stimulated basal respiration and ATP hydrolysis, but inhibited net state 3 (ADP-stimulated) respiration and Ca(2+) uptake, by collapsing the membrane potential at low doses (1-10μM). Uncoupled mitochondrial respiration and basal respiration of SMPs were inhibited by the three drugs at concentrations at least one order of magnitude higher and with different efficacy: MitoVES>α-TEA>α-TOS. At high doses (>10μM), the respiratory complex II (CII) was the most sensitive MitoVES target. Acting as an uncoupler at low doses, this agent stimulated total O(2) uptake, collapsed ∆ψ(m), inhibited oxidative phosphorylation and induced ATP depletion in rodent and human cancer cells more potently than in normal rat hepatocytes. These findings revealed that in situ tumor mitochondria are preferred targets of the drug, indicating its clinical relevance.
Authors:
Sara Rodríguez-Enríquez; Luz Hernández-Esquivel; Alvaro Marín-Hernández; Lan-Feng Dong; Emmanuel T Akporiaye; Jiri Neuzil; Stephen J Ralph; Rafael Moreno-Sánchez
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-22
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1817     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2013-03-08     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1597-607     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Affiliation:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Tlalpan, Mexico.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / chemistry
Animals
Calcium / metabolism
Cattle
Cell Line, Tumor
Cell Respiration / drug effects
Electron Transport Complex I / metabolism
Electron Transport Complex II / metabolism
Humans
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects*,  physiology
Neoplasms / drug therapy*
Rats
Vitamin E / analogs & derivatives*
Grant Support
ID/Acronym/Agency:
5R01CA120552/CA/NCI NIH HHS; R01 CA120552/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
1406-18-4/Vitamin E; 56-65-5/Adenosine Triphosphate; 7440-70-2/Calcium; EC 1.3.5.1/Electron Transport Complex II; EC 1.6.5.3/Electron Transport Complex I; EC 1.6.5.3/respiratory complex II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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