Mitochondria Play a Central Role in Apoptosis Induced by α-Tocopheryl Succinate, an Agent with Antineoplastic Activity:  Comparison with Receptor-Mediated Pro-Apoptotic Signaling

• Published in: Biochemistry (Easton) Vol. 42; no. 14; pp. 4277 - 4291
• Main Authors: Weber, Tobias, Dalen, Helge, Andera, Ladislav, Nègre-Salvayre, Anne, Augé, Nathalie, Sticha, Martin, Lloret, Ana, Terman, Alexei, Witting, Paul K, Higuchi, Masahiro, Plasilova, Magdalena, Zivny, Jan, Gellert, Nina, Weber, Christian, Neuzil, Jiri
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.04.2003
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Caspase 9; Caspases - metabolism; Humans; Jurkat Cells; Medicin och hälsovetenskap; Mitochondria - physiology; Signal Transduction - physiology; Tocopherols; Vitamin E - analogs & derivatives; Vitamin E - pharmacology
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi020527j

α-Tocopheryl succinate (α-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 α-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 α-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 α-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to α-TOS, by regulation of α-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with α-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 α-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.