Arsenic trioxide induces apoptosis in leukemia/lymphoma cell lines via the CD95/CD95L system.
Although arsenic trioxide (As2O3) has been shown to be an effective anticancer agent for acute promyelocytic leukemia (APL), its mechanisms of action as well as its effect on other leukemias than APL remain unclear. We studied in vitro effects of As2O3 at low concentrations (1.0-2.0 microM) on two human leukemia/lymphoma cell lines, HL-60, an acute myeloid leukemia cell line, and RL, a B-cell lymphoma cell line. As2O3 inhibited proliferation of HL-60 cells and RL cells to the similar degree to the reported inhibition by an APL cell line, NB4. As2O3-treated cell lines exhibited typical morphologic changes of apoptosis such as nuclear condensation and apoptotic bodies, and a cell cycle arrest at the subG1 phase. As2O3-treated cell lines also showed upregulation of CD95/CD95L expression and activation of caspases 8 and 3. Treatment of these cells with anti-CD95 antibodies capable of blocking the CD95 signaling pathway ameliorated As2O3-induced apoptosis. These data suggest that As2O3 can inhibit growth of leukemia/lymphoma cells by inducing the cell cycle arrest and apoptosis that is partially mediated by the CD95/CD95L system.
Zhu
Jiebin
J
Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Takara-machi 13-1, Kanazawa 920-8641, Japan.
Okumura
Hirokazu
H
Ohtake
Shigeki
S
Nakamura
Shinobu
S
Nakao
Shinji
S
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D053222:Fas Ligand Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001152:Arsenicals; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D010087:Oxides; 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