title: Induction of apoptosis by dexrazoxane (ICRF-187) through caspases in the absence of c-jun expression and c-Jun NH2-terminal kinase 1 (JNK1) activation in VM-26-resistant CEM cells.
abstract: Dexrazoxane (ICRF-187) is an inhibitor of the catalytic activity of DNA topoisomerase II (topo II) that does not stabilize DNA-topo II covalent complexes. Here, we examined cytotoxic signaling by ICRF-187 in human leukemic CEM cells and a teniposide (VM-26)-resistant subline, CEM/VM-1. Treatment of CEM and CEM/VM-1 cells with ICRF-187 induced apoptotic cell death characterized by internucleosomal DNA fragmentation, nuclear condensation, and induction of at least caspase-3- and -7-like protease activities (but not caspase 1). Treatment of these cells with Z-Asp-2,6-dichlorobenzoyloxymethyl-ketone, a potent inhibitor of apoptosis, inhibited ICRF-187-induced DEVD-specific caspase activity and apoptosis in a concentration-dependent manner. ICRF-187-induced apoptosis in CEM cells was associated with transient induction of c-jun and activation of c-Jun NH2-terminal kinase 1 (JNK1). However, CEM/VM-1 cells, which were 3-fold more sensitive than CEM cells to ICRF-187 due to a decrease in topo II activity, exhibited ICRF-187-induced apoptosis in the absence of c-jun induction and JNK1 activation. These results indicate that catalytic inhibition of topo II by ICRF-187 leads to apoptosis through at least a caspase-3- and -7-like protease-dependent mechanism and suggest that c-jun and JNK1 are not required in ICRF-187-induced apoptosis in CEM cells.
authors.affiliation: Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607-7173, USA.
authors.forename: T
authors.initials: T
authors.lastname: Khélifa
authors.forename: W T
authors.initials: WT
authors.lastname: Beck
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011929:Razoxane / Q000494:pharmacology*; D015398:Signal Transduction; D013713:Teniposide / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D059005:Topoisomerase II Inhibitors; C117865:benzyloxycarbonyl-asparagine; D011929:Razoxane; D001216:Asparagine; D013713:Teniposide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases