The Catalytic DNA Topoisomerase II Inhibitor Dexrazoxane (ICRF-187) Induces Differentiation and Apoptosis in Human Leukemia K562 Cells

Abstract

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.

Actin reorganization in CHO AA8 cells undergoing mitotic catastrophe and apoptosis induced by doxorubicin

“…As a result, multilobulated cells markedly increased in volume and ploidy occurred. Actin cytoskeleton was well-preserved (50). The results showing the existence of the undamaged network of actin and tubulin filaments in CHO AA8 cells undergoing mitotic catastrophe were demonstrated in our recent studies.…”

The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway

“…ICRF-193 is known to kill yeast cells expressing hTOP2 and induces apoptosis in mammalian cells (23,39). Studies in yeast have demonstrated that ICRF-193-induced killing is unrelated to inhibition of the catalytic activity of TOP2 but is consistent with trapping of TOP2 into potentially lethal complexes (39).…”

“…This result suggests that preferential degradation of TOP2␤ over TOP2␣ is not due to preferential inhibition of TOP2␤ over TOP2␣ by 26S Proteasome Is Involved in hTOP2␤ Down-Regulation. is known to induce apoptotic cell death (23). Degradation of TOP2␤ could be due to the indirect result of cell death.…”

Quantitative Fluorescence Imaging Approach for the Study of Polyploidization in Hepatocytes

“…Whereas both situations are unlikely to take place in physiological liver growth, disruption of specific pathways indicates possible relevant mechanisms involving, e.g., p21 (Waldman et al 1996), p53 (Arora and Iversen 2000), and Skp2 (Nakayama et al 2000). Topoisomerase II inhibition (Hasinoff et al 2000), halted cyclin B1 nuclear localization (Barnes et al 2001), and inactivation of membrane protein kinase (Zong et al 2000) are other avenues to explore. These mechanisms can now be addressed in hepatocytes, taking advantage of fluorescence imaging.…”