Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro

Arsenic trioxide (As 2 O 3 ) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As 2 O 3 in CADO‐ES Ewing's sarcoma (ES), JK‐GMS peripheral primitive neuroectodermal tumor (PNET), and SH‐SY5Y neuroblastoma cells, as they share common histogenetic backgrounds. As 2 O 3 at low concentrations (0.1–1 μM) induced SH‐SY5Y differentiation, and whereas PNET cells acquired a slightly differentiated phenotype, change was minimal in ES cells. Extracellular signal‐regulated kinase 2 (ERK2) was activated at low As 2 O 3 concentrations, and PD98059, an inhibitor of MEK‐1, blocked SH‐SY5Y cell differentiation by As 2 O 3 . High concentrations (2–10 μM) of As 2 O 3 induced the apoptosis in all three cell lines, and this was accompanied by the activation of c ‐ jun N‐terminal kinase. The generation of H 2 O 2 and activation of caspase 3 were identified as critical components of As 2 O 3 ‐induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As 2 O 3 ‐induced apoptosis in JK‐GMS cells. The overall effects of As 2 O 3 strongly suggest that it has therapeutic potential for the treatment of ES/PNET.