Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic
Tobias Weber1, Helge Dalen, Ladislav Andera
1Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Munich, Germany.
Abstract:
alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with alpha-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For alpha-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to alpha-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to alpha-TOS, by regulation of alpha-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with alpha-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which alpha-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.
Insights
Alpha-tocopheryl succinate (alpha-TOS), a vitamin E derivative, induces cancer cell death by damaging mitochondria. Its pro-apoptotic effects are mediated through caspase activation and mitochondrial pathways, suggesting potential as an anticancer agent.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Alpha-tocopheryl succinate (alpha-TOS) is a vitamin E analog with demonstrated anti-cancer properties.
- Previous research suggested alpha-TOS induces apoptosis via organelle destabilization, but the precise mechanisms remained unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying alpha-TOS-induced apoptosis in cancer cells.
- To investigate the role of mitochondria and caspases in alpha-TOS-mediated cell death.
Main Methods:
- Treatment of cells with alpha-TOS and assessment of mitochondrial structure, free radical generation, and caspase activation.
- Utilizing caspase inhibitors, mtDNA-deficient cells, and Bcl-2 family members to dissect apoptotic pathways.
- Evaluating the effects of co-treatment with alpha-TOS and anti-Fas IgM.
Main Results:
- Alpha-TOS treatment altered mitochondrial structure, increased free radicals, and activated caspases, cytochrome c, and Smac/Diablo.
- Apoptosis induction by alpha-TOS was dependent on caspase-9 and mitochondrial integrity, distinguishing it from Fas/TRAIL pathways.
- Mitochondria-targeted radical scavengers and Bcl-2 family proteins modulated alpha-TOS-induced apoptosis, confirming mitochondria's central role.
Conclusions:
- Alpha-TOS triggers cancer cell death primarily through mitochondrial damage and caspase activation.
- The findings provide mechanistic insights into alpha-TOS's anti-cancer activity.
- Alpha-TOS shows promise as a potential anticancer therapeutic or adjuvant therapy.
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