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

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 apoptocic 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-dichlorobenzomethyl-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-I 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. (C) 1999 Elsevier Science Inc.