Premium
Clinically tolerable concentrations of arsenic trioxide induce p53‐independent cell death and repress NF‐κB activation in Ewing sarcoma cells
Author(s) -
Mathieu Julie,
Besançon Françoise
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21970
Subject(s) - arsenic trioxide , cancer research , apoptosis , programmed cell death , sarcoma , mcl1 , medicine , kinase , biology , downregulation and upregulation , pathology , gene , microbiology and biotechnology , genetics
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 (As 2 O 3 ), a compound known to induce differentiation and apoptosis of other types of malignant cells. The authors report that As 2 O 3 uniformly induced death of 6 ES‐derived cell lines irrespective of their p53 status. As 2 O 3 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. As 2 O 3 also decreased basal and cytokine‐induced NF‐κB activity. Since the authors previously demonstrated that NF‐κB exerts an antiapoptotic action in ES cells, As 2 O 3 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 As 2 O 3 as a good candidate for future protocols to improve treatments of Ewing sarcomas, irrespective of the p53 status of the tumor. © 2006 Wiley‐Liss, Inc.