Exposure of MDA-MB-231 and MCF-7/VP human
breast carcinoma cells to the
anthracyclines doxorubicin and
WP631 induced
polyploidy, formation of multinucleated cells and cell death by mitotic catastrophe through
caspase-dependent and
caspase-independent mechanisms. In both cell lines, the antiproliferative effect of
WP631 was higher than that of
doxorubicin and a transient halt in G(2)/M was observed without cell senescence, while p53-dependent apoptosis did not occur in these cells. Mitotic catastrophe was linked to
necrosis, but also to apoptosis-like death, estimated by differential cell staining with
annexin-V-
fluorescein and
propidium iodide.
Drug-induced changes in the expression of c-myc and p21(WAF1), and in their respective
protein levels, were observed. They depended on the cell line, the
anthracycline used and its concentration, and they were consistent with the cell cycle progression through G(2) to mitosis. Significant activation of
caspase-2 and
caspase-3 was only observed in MDA-MB-231 cells treated with
doxorubicin but not with
WP631, indicating that
caspases may be not mandatory for the occurrence of cell death through mitotic catastrophe. In MCF-7/VP cells, which do not express functional
caspase-3, mitotic catastrophe was also induced.