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.