Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype

Cdc2 and Cdk2 play critical roles in low dose doxorubicin-induced cell death through mitotic catastrophe but not in high dose doxorubicin-induced apoptosis

“…We recently showed that different death modes can be induced in response to different doses of doxorubicin: a slow cell death through mitotic catastrophe is induced by LD doxorubicin, while a rapid apoptosis is induced by HD doxorubicin [9]. Huh-7 cells treated with LD doxorubicin undergo abnormal mitosis and finally die though mitotic catastrophe accompanied by the formation of multiple micronuclei and the loss of membrane integrity.…”

“…For example, fluorouracil treatment of colorectal cells induces mitotic catastrophe independent of apoptosis [5], and mitotic catastrophe has been shown to be independent of Bcl-2 and apoptosis in etoposide-treated human epithelial cells [22]. We recently showed that sustained activation of p38, JNK, and caspases are observed in HD doxorubicin-induced apoptosis but not in LD doxorubicin-induced cell death through mitotic catastrophe [9], suggesting that differential regulatory mechanisms may be activated by different doses of doxorubicin, leading to either apoptosis or cell death mitotic catastrophe. In this study, we investigated whether the differential modulation of cell cycle regulators could contribute to the induction of the two types of cell death by LD and HD doxorubicin.…”

“…However, more recent studies have redefined mitotic catastrophe as an abnormal mitosis that leads to cell death (which can occur through necrosis or apoptosis) rather than an actual form of cell death [7,8]. We recently showed in human hepatocellular carcinoma (HCC) cells that LD doxorubicin induces cell death through mitotic catastrophe, and that this is a morphologically distinct death mode from the apoptosis induced by HD doxorubicin [9]. However, the molecular basis of this cell death through mitotic catastrophe is largely unknown, as are the underlying mechanisms by which two distinct modes of cell death are induced by different doses of the same anti-cancer drug.…”

A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells

“…Senescence is considered largely p53-dependent, while the onset of mitotic catastrophe is not [11,12]. Several DNA-binding drugs have been reported to produce mitotic catastrophe in both cells containing wild-type p53 and those bearing mutated or deleted p53 genes [13][14][15][16][17]. Mitotic catastrophe occurs in tumor cells treated with various antitumour drugs or radiation [7,13,14,[16][17][18][19][20][21].…”

Bcl-xL blocks high dose doxorubicin-induced apoptosis but not low dose doxorubicin-induced cell death through mitotic catastrophe

“…Although the chemotherapeutic effect of doxorubicin has focused primarily on its ability to induce apoptosis, we recently showed that, in hepatoma cells, low dose (LD) doxorubicin induces cell death through mitotic catastrophe, whereas high dose (HD) doxorubicin induces apoptosis [7]. 'Mitotic cell death' or 'cell death through mitotic catastrophe' generally refers to death caused by abnormal mitosis [8,9] but it has not been well-characterized.…”