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  • α-tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability

    Author(s)
    Neuzil, Jiri
    Zhao, Ming
    Ostermann, Georg
    Sticha, Martin
    Gellert, Nina
    Weber, Christian
    W. Eaton, John
    T. Brunk, Ulf
    Griffith University Author(s)
    Neuzil, Jiri
    Gellert, Nina
    Year published
    2002
    Metadata
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    Abstract
    Certain vitamin E analogues, such as a-tocopheryl succinate (a-TOS), exhibit in vivo anti-tumour activity and, in vitro , induce apoptosis of cultured tumour cells. In the present study we report that these effects may be explained, at least in part, by destabilization of lysosomal membranes. a-TOS, but not a-tocopheryl acetate or a-tocopherol (a-TOH), induced early lysosomal destabilization followed by apoptosis. Similar effects were observed with b-TOS, whereas b-TOH was inactive. Cathepsin D-deficient cells were more resistant to a-TOS than their normal counterparts, and featured delayed caspase activation. Possible ...
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    Certain vitamin E analogues, such as a-tocopheryl succinate (a-TOS), exhibit in vivo anti-tumour activity and, in vitro , induce apoptosis of cultured tumour cells. In the present study we report that these effects may be explained, at least in part, by destabilization of lysosomal membranes. a-TOS, but not a-tocopheryl acetate or a-tocopherol (a-TOH), induced early lysosomal destabilization followed by apoptosis. Similar effects were observed with b-TOS, whereas b-TOH was inactive. Cathepsin D-deficient cells were more resistant to a-TOS than their normal counterparts, and featured delayed caspase activation. Possible detergent and lysosomotropic effects of a- and b-TOS were suggested by their haemolytic activity in an in vitro test and their release of b- galactosidase from isolated lysosomes, whereas the non-succinylated analogues were inactive. The pro-apoptotic activity of a-TOS was pH-dependent, being greater at lower pH, typical of the interstitium of solid tumours. These findings indicate that lysosomal destabilization may partially or fully explain the induction of apoptosis in cultured cells by a-TOS and the mechanism whereby this agent exerts in vivo anti-tumour effects.
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    Journal Title
    Biochemical Journal
    Volume
    362
    DOI
    https://doi.org/10.1042/bj3620709
    Copyright Statement
    © The Author(s) 2002.
    Subject
    Chemical Sciences
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/6787
    Collection
    • Journal articles

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