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

• Published in: FEBS letters 2006-09, Vol.580 (20), p.4969-4975
• Main Authors: Jung, Hyun Sook, Kim, Han-Seong, Lee, Min-Jae, Shin, Hee Young, Ahn, Hyo Seop, Ryu, Kyung-Ha, Seoh, Ju-Young, Kim, Chong Jai, Jang, Ja June
• Format: Article
• Language: English
• Subjects: acute promyelocytic leukemia; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; APL; Apoptosis - drug effects; Apoptosis - physiology; Arsenic trioxide; Arsenicals - metabolism; Arsenicals - pharmacology; As2O3; c-jun N-terminal kinase; Cell Differentiation - physiology; Cell Line, Tumor - drug effects; Enzyme Activation; Enzyme Inhibitors - metabolism; ERK1/2; Ewing's sarcoma; Ewing's sarcoma/peripheral primitive neuroectodermal tumor; extracellular signal-regulated kinase 1/2; FGF2; fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Flavonoids - metabolism; Humans; In Vitro Techniques; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - metabolism; MAPKs; mitogen activated protein kinases; Mitogen-Activated Protein Kinase 1 - metabolism; neuroblastoma; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neurons - cytology; Neurons - physiology; Oxides - metabolism; Oxides - pharmacology; peripheral primitive neuroectodermal tumor; Phenotype; PNET; reactive oxygen species; ROS; Sarcoma, Ewing - metabolism; Sarcoma, Ewing - pathology
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2006.07.077

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.