title: Molecular mechanism for the selective impairment of cancer mitochondrial function by a mitochondrially targeted vitamin E analogue.
abstract: 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.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología, Tlalpan, Mexico.
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Enríquez
authors.forename: Luz
authors.initials: L
authors.lastname: Hernández-Esquivel
authors.forename: Alvaro
authors.initials: A
authors.lastname: Marín-Hernández
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Emmanuel T
authors.initials: ET
authors.lastname: Akporiaye
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Sánchez
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy*; D051381:Rats; D014810:Vitamin E / Q000031:analogs & derivatives*
chemical_list: C478189:respiratory complex II; D014810:Vitamin E; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D002118:Calcium