Uncoupling of incorporation of ascorbic acid and apoptosis induction.
Exposure of human promyelocytic leukemic HL-60 cells to millimolar concentration of sodium ascorbate induced apoptotic cell death. The extent of apoptosis induction was a positive function of temperature at the time of exposure. The incorporation of [1-14C] ascorbic acid into the cytosolic fraction of HL-60 cells was also temperature-dependent, and competitively inhibited by active analogs (L-ascorbic acid, sodium L-ascorbate, D-isoascorbic acid, sodium 6-beta-O-galactosyl-L-ascorbate, sodium 5,6-benzylidene-L-ascorbate), but not by inactive analogs (L-ascorbic acid-2-phosphate magnesium, L-ascorbic acid 2-sulfate). Calcium depletion, which had considerably reduced the apoptosis-inducing activity of sodium ascorbate, did not affect the intracellular incorporation of [14C] ascorbic acid. These data suggests that cell death might not be simply induced by the intracellular incorporation of ascorbate, but rather initiated by the rapid elevation of intracellular Ca2+ concentration, possibly mediated by an as yet unidentified temperature-sensitive mechanism.
Department of Biochemistry, School of Medicine, Showa University, Tokyo, Japan.
Y
Y
Amano
H
H
Sakagami
T
T
Tanaka
Y
Y
Yamanaka
Y
Y
Nishimoto
M
M
Yamaguchi
M
M
Takeda
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002250:Carbon Radioisotopes; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D013237:Stereoisomerism; D013696:Temperature; D013997:Time Factors
D002250:Carbon Radioisotopes; D001205:Ascorbic Acid; D002118:Calcium