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

Abstract

Arsenic trioxide (As 2O 3) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As 2O 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 2O 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 2O 3 concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As 2O 3. High concentrations (2-10 μM) of As 2O 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 2O 2 and activation of caspase 3 were identified as critical components of As 2O 3-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As 2O 3-induced apoptosis in JK-GMS cells. The overall effects of As 2O 3 strongly suggest that it has therapeutic potential for the treatment of ES/PNET. © 2006 Federation of European Biochemical Societies.