Clinically tolerable concentrations of arsenic trioxide induce p53-independent cell death and repress NF-kappa B activation in Ewing sarcoma cells.
Ewing sarcoma (ES), a highly malignant pediatric tumor, is consistently associated with translocations that fuse the EWS gene with a member of the ETS family gene, most commonly FLI-1. Despite significant advances with multiagent chemotherapy, surgery and radiotherapy, about 40% of ES patients still die from the disease. It is therefore necessary to explore novel agents for possible treatment of this tumor. Here the authors investigated the sensitivity of ES cells to clinically tolerable concentrations of arsenic trioxide (As2O3), a compound known to induce differentiation and apoptosis of other types of malignant cells. The authors report that As2O3 uniformly induced death of 6 ES-derived cell lines irrespective of their p53 status. As2O3 resulted in an apoptotic phenotype which was inhibited by the broad-spectrum caspase inhibitor ZVAD-fmk. These effects correlated with prolonged c-jun N-terminal kinase activation, which is a signal for apoptosis in ES cells. As2O3 also decreased basal and cytokine-induced NF-kappa B activity. Since the authors previously demonstrated that NF-kappa B exerts an antiapoptotic action in ES cells, As2O3 treatment may also result in a sensitization of these cells to other drugs used in combination therapy. These effects, combined with its antiangiogenic action, define As2O3 as a good candidate for future protocols to improve treatments of Ewing sarcomas, irrespective of the p53 status of the tumor.
Mathieu
Julie
J
INSERM Unité 685, IFR 105, Hopital St-Louis, 1 avenue Claude Vellefaux, Paris cedex, France.
Besançon
Françoise
F
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D000077237:Arsenic Trioxide