Mechanism of α-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells

Shinji Yamamoto, Hiroshi Tamai, Rumi Ishisaka, Tomoko Kanno, Kayo Arita, Hirotsugu Kobuchi, Kozo Utsumi

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

Selective induction of apoptosis in tumor cells is important for treating patients with cancer. Because oxidative stress plays an important role in the process of apoptosis, we studied the effect of α-tocopheryl succinate (VES) on the fate of cultured human promyelocytic leukemia cells (HL-60). The presence of fairly low concentrations of VES inhibited the growth and DNA synthesis of HL-60 cells, and also induced their apoptosis via a mechanism that was inhibited by z-VAD-fluoromethylketone (z-VAD-fmk), an inhibitor of pan-caspases. VES activated various types of caspases, including caspase-3, 6, 8, and 9, but not caspase-1. VES triggered the reaction leading to the cleavage of Bid, a member of the death agonist Bcl-2 family, and released cytochrome c (Cyt.c) from the mitochondria into the cytosol by a z-VAD-fmk-inhibitable mechanism. VES transiently increased the intracellular calcium level [Ca2+](i) and stimulated the release of Cyt.c in the presence of inorganic phosphate (Pi). However, high concentrations of VES (≃100 μM) hardly induced swelling of isolated mitochondria but depolarized the mitochondrial membrane potential by a cyclosporin A (CsA)-insensitive mechanism. These results indicate that VES-induced apoptosis of HL-60 cells might be caused by activation of the caspase cascade coupled with modulation of mitochondrial membrane function.

Original languageEnglish
Pages (from-to)407-418
Number of pages12
JournalFree Radical Research
Volume33
Issue number4
DOIs
Publication statusPublished - Jan 1 2000
Externally publishedYes

Keywords

  • Apoptosis
  • Bid
  • Caspase
  • Cytochrome c
  • HL-60 cells
  • Membrane permeability transition
  • Mitochondria
  • α-tocopheryl succinate

ASJC Scopus subject areas

  • Biochemistry

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