Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro |
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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 |
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Institution: | Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, 110-799 Seoul, Korea. |
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Abstract: | 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 microM) 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 microM) 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. |
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Keywords: | As2O3 arsenic trioxide APL acute promyelocytic leukemia NB neuroblastoma ES Ewing’s sarcoma PNET peripheral primitive neuroectodermal tumor MAPKs mitogen activated protein kinases ERK1/2 extracellular signal-regulated kinase 1/2 JNK c-jun N-terminal kinase FGF2 fibroblast growth factor 2 ROS reactive oxygen species |
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