Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic activity: comparison with receptor-mediated pro-apoptotic signaling.
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.
Weber
Tobias
T
Institute for Prevention of Cardiovascular Diseases, Ludwig Maximilians University, Munich, Germany.
Dalen
Helge
H
Andera
Ladislav
L
Nègre-Salvayre
Anne
A
Augé
Nathalie
N
Sticha
Martin
M
Lloret
Ana
A
Terman
Alexei
A
Witting
Paul K
PK
Higuchi
Masahiro
M
Plasilova
Magdalena
M
Zivny
Jan
J
Gellert
Nina
N
Weber
Christian
C
Neuzil
Jiri
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014810:Vitamin E; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D024505:Tocopherols