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
Year published
2002
Metadata
Show full item recordAbstract
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 ...
View more >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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View more >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
Copyright Statement
© The Author(s) 2002.
Subject
Chemical Sciences
Biological Sciences
Medical and Health Sciences