• myGriffith
    • Staff portal
    • Contact Us⌄
      • Future student enquiries 1800 677 728
      • Current student enquiries 1800 154 055
      • International enquiries +61 7 3735 6425
      • General enquiries 07 3735 7111
      • Online enquiries
      • Staff phonebook
    View Item 
    •   Home
    • Griffith Research Online
    • Journal articles
    • View Item
    • Home
    • Griffith Research Online
    • Journal articles
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

  • All of Griffith Research Online
    • Communities & Collections
    • Authors
    • By Issue Date
    • Titles
  • This Collection
    • Authors
    • By Issue Date
    • Titles
  • Statistics

  • Most Popular Items
  • Statistics by Country
  • Most Popular Authors
  • Support

  • Contact us
  • FAQs
  • Admin login

  • Login
  • Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II

    Thumbnail
    View/Open
    67469_1.pdf (1022.Kb)
    Author(s)
    Dong, Lan-Feng
    Jameson, Victoria JA
    Tilly, David
    Cerny, Jiri
    Mahdavian, Elahe
    Marin-Hernandez, Alvaro
    Hernandez-Esquivel, Luz
    Rodriguez-Enriquez, Sara
    Stursa, Jan
    Witting, Paul K
    Stantic, Bela
    Rohlena, Jakub
    Truksa, Jaroslav
    Kluckova, Katarina
    Dyason, Jeffrey C
    Ledvina, Miroslav
    Salvatore, Brian A
    Moreno-Sanchez, Rafael
    Coster, Mark J
    Ralph, Stephen J
    Smith, Robin AJ
    Neuzil, Jiri
    Griffith University Author(s)
    Stantic, Bela
    Neuzil, Jiri
    Ralph, Stephen J.
    Year published
    2011
    Metadata
    Show full item record
    Abstract
    Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC50 of 80 孬 whereas the electron transfer from CII to CIII was inhibited with IC50 ...
    View more >
    Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC50 of 80 孬 whereas the electron transfer from CII to CIII was inhibited with IC50 of 1.5 孮 The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1a fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser68 within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.
    View less >
    Journal Title
    Journal of Biological Chemistry
    Volume
    286
    Issue
    5
    DOI
    https://doi.org/10.1074/jbc.M110.186643
    Copyright Statement
    This research was originally published in Journal of Biological Chemistry (JBC). Lan-Feng Dong etc, Mitochondrial Targeting of Vitamin E Succinate Enhances Its Pro-apoptotic and Anti-cancer Activity via Mitochondrial: Complex II, Journal of Biological Chemistry (JBC), 2011; Vol. 286(5), pp. 3717-3728. Copyright the American Society for Biochemistry and Molecular Biology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitve version.
    Subject
    Chemical sciences
    Biological sciences
    Biomedical and clinical sciences
    Medical microbiology not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/39853
    Collection
    • Journal articles

    Footer

    Disclaimer

    • Privacy policy
    • Copyright matters
    • CRICOS Provider - 00233E
    • TEQSA: PRV12076

    Tagline

    • Gold Coast
    • Logan
    • Brisbane - Queensland, Australia
    First Peoples of Australia
    • Aboriginal
    • Torres Strait Islander