The molecular mechanism of arsenic trioxide-induced apoptosis and oncosis in leukemia/lymphoma cell lines.
The mechanisms of As(2)O(3)-induced apoptosis are very complex. In the present study, we investigated the molecular mechanism of As(2)O(3) in vitro at low concentration (0.25-2.0 micro M) on three human leukemia/lymphoma cell lines: HL-60, RL and K562. As(2)O(3) inhibited the growth of these cell lines significantly. During As(2)O(3) treatment, two forms of cell death, apoptosis in HL-60 and RL and oncosis in K562, were found by morphological study. In HL-60 and RL, cell cycle analysis showed, at a distinct SubG1 region, that CD95 and CD95 ligand (CD95L) expression was upregulated, caspase 8 and caspase 3 were activated, and Bcl-2 protein expression was downregulated. On the other hand, in K562, the cell cycle was arrested at the G2+M phase, CD95/CD95L expression was upregulated, caspase 8 and caspase 3 were activated, but Bcl-2 expression was not changed as compared with untreated cells. These findings suggest that the CD95/CD95L pathway is involved in cell killing by As(2)O(3). Using anti-CD95 IgG monoclonal antibody (anti-CD95 MoAb) or specific caspase inhibitor ZVAD-fmk to block the CD95 pathway, the cell death induced by As(2)O(3) was partially blocked in each cell line. These results suggest that As(2)O(3) inhibits the growth of these leukemia/lymphoma cell lines by inducing apoptosis or oncosis that is partially mediated by the CD95/CD95L pathway.
Zhu
Jiebin
J
Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Okumura
Hirokazu
H
Ohtake
Shigeki
S
Nakamura
Shinobu
S
Nakao
Shinji
S
D000208:Acute Disease; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D053222:Fas Ligand Protein; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001152:Arsenicals; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000077237:Arsenic Trioxide