Cholesteryl-hemisuccinate-induced apoptosis of promyelocytic leukemia HL-60 cells through a cyclosporin A-insensitive mechanism

Katsuhiko Yamada, Kayo Arita, Hirotsugu Kobuchi, Shinji Yamamoto, Tamotsu Yoshioka, Hiroshi Tamai, Kozo Utsumi

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


We reported previously that α-tocopheryl-succinate (VES) induced apoptosis of cultured human promyelocytic leukemia cells (HL-60) (Free Radic Res 2000;33:407-18). We have now studied the effect of cholesteryl-hemisuccinate (CS) on the fate of HL-60 cells to clarify whether CS has an effect similar to that of VES. CS inhibited the growth of HL-60 cells without differentiation to granulocytes and induced DNA fragmentation and ladder formation. CS inhibited the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt) and initiated the activation of a caspase cascade. CS triggered the reaction leading to the cleavage of Bid and also released cytochrome c (Cyt. c) from mitochondria. In addition, CS induced mitochondrial membrane depolarization and translocation of Bax to mitochondria in HL-60 cells. However, CS did not induce an increase in the concentration of intracellular calcium ions in HL-60 cells. The membrane depolarization, Cyt. c release, and DNA fragmentation were inhibited by z-VAD-fluoromethylketone (z-VAD-fmk), a pan-caspase inhibitor, but not by cyclosporin A, an inhibitor of membrane permeability transition. These results suggested that CS-induced apoptosis of HL-60 cells might be caused by inhibiting Akt phosphorylation following cleavage of Bid through caspase-8 activation and subsequently via an Apaf complex-caspase cascade pathway.

Original languageEnglish
Pages (from-to)339-348
Number of pages10
JournalBiochemical Pharmacology
Issue number3
Publication statusPublished - Feb 1 2003


  • Akt
  • Apoptosis
  • Bid
  • Caspase
  • Cholesteryl-hemisuccinate
  • Cytochrome c
  • HL-60 cells
  • Membrane permeability transition

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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