Mitochondria play a central role in apoptosis induced by a-tocopheryl succinate, an agent with antineoplastic activity Comparison with receptor-mediated pro-apoptotic signaling

• Published in: Biochemistry (Easton) Vol. 42; no. 14; p. 4277
• Main Authors: Weber, A, Dalen, Helge, Andera, L, Nègre-Salvayre, A, Augé, N, Sticha, M, Loret, A, Terman, Alexei, Witting, PK, Higuchi, M, Plasilova, M, Zivny, J, Gellert, N, Weber, C, Neuzil, Jiri
• Format: Journal Article
• Language: English
• Published: 2003
• Subjects: MEDICIN; MEDICINE
• ISSN: 1520-4995; 0006-2960
• DOI: 10.1021/bi020527j

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