Arsenic trioxide (As2O3) induces both the differentiation and apoptosis of acute promyelocytic leukemia cells in a concentration dependent manner. We assessed the effects of As2O3 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. As2O3 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 As2O3 concentrations, and PD98059, an inhibitor of MEK-1, blocked SH-SY5Y cell differentiation by As2O3. High concentrations (2-10 μM) of As2O3 induced the apoptosis in all three cell lines, and this was accompanied by the activation of c-jun N-terminal kinase. The generation of H2O2 and activation of caspase 3 were identified as critical components of As2O3-induced apoptosis in all of the above cell lines. Fibroblast growth factor 2 enhanced As2O3-induced apoptosis in JK-GMS cells. The overall effects of As2O3 strongly suggest that it has therapeutic potential for the treatment of ES/PNET.
Bibliographical noteFunding Information:
This work was supported in part by Grant No. R01-2001-000-00128-0 from the Korea Science & Engineering Foundation and in part by the BK21 Program for Medicine, Dentistry and Pharmacy, 2003.
- Arsenic trioxide
- Ewing's sarcoma/peripheral primitive neuroectodermal tumor