The bisdioxopiperazines
ICRF-187 (
dexrazoxane),
ICRF-193, and
ICRF-154 are catalytic noncleavable complex-forming inhibitors of
DNA topoisomerase II that do not produce
protein-linked
DNA strand breaks. In this study, we showed that bisdioxopiperazines induced erythroid differentiation, inhibited human
leukemia K562 cell growth, and caused a slow induction of apoptosis.
Dexrazoxane treatment caused
DNA endoreduplication resulting in large highly
polyploid cells. This result suggested the lack of
a DNA topoisomerase II activity-based cell cycle checkpoint. The percentage of K562 cells that became apoptotic was much larger than the percentage of cells that stained for
hemoglobin, suggesting that prior differentiation was not required for induction of apoptosis. Use of the
Bcr-Abl tyrosine kinase inhibitor
STI-571 resulted in a reduction in Bcl-xL levels and potentiation of
dexrazoxane-induced apoptosis related to an earlier onset and more extensive cleavage of
caspase-3. These results indicated that
dexrazoxane-induced apoptosis is associated with a
caspase-3 activation/cleavage pathway. In addition, these results were consistent with the antiapoptotic signaling function of Bcr-Abl to regulate expression of Bcl-xL. The ability of
dexrazoxane to induce differentiation and apoptosis suggests that bisdioxopiperazines may be useful in treating some types of
leukemia.