title: Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells.
abstract: It has been suggested that oxidative stress plays a major role in various forms of cell death, including necrosis and apoptosis. We have previously reported that fluoride (NaF) induces apoptosis in HL-60 cells by caspase-3 activation. The main focus of this investigation was to arrive at a possible pathway of the apoptosis induced by NaF upstream of caspase-3, because the mechanism is still unknown. The present study showed that after exposure to NaF, there was an increase in MDA and 4-HNE and a loss of mitochondrial membrane potential (deltaPsi(m)) was also observed in NaF-treated cells. There was a significant increase in cytosolic cytochrome c, which is released from the mitochondria. We have reported a downregulation of Bcl-2 protein in NaF-treated cells. The antioxidants N-acetyl cysteine (NAC), glutathione (GSH) protected the cells from loss of deltaPsi(m), and there was no cytochrome c exit or Bcl-2 downregulation, and we suggest that these antioxidants prevent apoptosis induced by NaF. These results suggested that perhaps NaF induced apoptosis by oxidative stress-induced lipid peroxidation, causing loss of deltaPsi(m), and thereby releasing cytochrome c into the cytosol and further triggering the caspase cascade leading to apoptotic cell death in HL-60 cells.
authors.affiliation: Regional Environment Division, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305 8506, Japan.
authors.forename: C D
authors.initials: CD
authors.lastname: Anuradha
authors.forename: S
authors.initials: S
authors.lastname: Kanno
authors.forename: S
authors.initials: S
authors.lastname: Hirano
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008054:Lipid Peroxides / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012969:Sodium Fluoride / Q000494:pharmacology*
chemical_list: D000447:Aldehydes; D000590:Amino Acid Chloromethyl Ketones; D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D008054:Lipid Peroxides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D008315:Malondialdehyde; D012969:Sodium Fluoride; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine