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 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.
Jung
Hyun Sook
HS
Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, 110-799 Seoul, Korea.
Kim
Han-Seong
HS
Lee
Min-Jae
MJ
Shin
Hee Young
HY
Ahn
Hyo Seop
HS
Ryu
Kyung-Ha
KH
Seoh
Ju-Young
JY
Kim
Chong Jai
CJ
Jang
Ja June
JJ
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010087:Oxides / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology
D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010087:Oxides; D016222:Fibroblast Growth Factor 2; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D000077237:Arsenic Trioxide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one