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

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

Weber, A (författare)

Dalen, Helge (författare): Östergötlands Läns Landsting,Linköpings universitet,Hälsouniversitetet,Patologi,Klinisk patologi och klinisk genetik

Andera, L (författare)

Nègre-Salvayre, A (författare)

Augé, N (författare)

Sticha, M (författare)

Loret, A (författare)

Terman, Alexei, 1957- (författare): Linköpings universitet,Hälsouniversitetet,Patologi

Witting, PK (författare)

Higuchi, M (författare)

Plasilova, M (författare)

Zivny, J (författare)

Gellert, N (författare)

Weber, C (författare)

Neuzil, Jiri, 1958- (författare): Linköpings universitet,Hälsouniversitetet,Patologi

(creator_code:org_t)

2003-03-22
2003
Engelska.
Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 42:14, s. 4277-4291

Relaterad länk:: https://urn.kb.se/re...; visa fler...; https://doi.org/10.1...; visa färre...

Abstract Ämnesord

Stäng

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.

Av författaren/redakt...: Weber, A; Dalen, Helge; Andera, L; Nègre-Salvayre, ...; Augé, N; Sticha, M; visa fler...; Loret, A; Terman, Alexei, ...; Witting, PK; Higuchi, M; Plasilova, M; Zivny, J; Gellert, N; Weber, C; Neuzil, Jiri, 19 ...; visa färre...

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