title: Arsenic trioxide concentration determines the fate of Ewing's sarcoma family tumors and neuroblastoma cells in vitro.
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.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, 110-799 Seoul, Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Jung
authors.forename: Han-Seong
authors.initials: HS
authors.lastname: Kim
authors.forename: Min-Jae
authors.initials: MJ
authors.lastname: Lee
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Shin
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
authors.forename: Kyung-Ha
authors.initials: KH
authors.lastname: Ryu
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Seoh
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Ja June
authors.initials: JJ
authors.lastname: Jang
mesh_terms: 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
chemical_list: 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