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.