Abstract
Although the phenomenon of mitotic catastrophe was first described more than 80 years ago, only recently has this term been used to explain a mechanism of cell death linked to delayed mitosis. Several mechanisms have been suggested for mitotic catastrophe development and cell fate. Depending on molecular perturbations, mitotic catastrophe can end in three types of cell death, namely apoptosis, necrosis, or autophagy. Moreover, mitotic catastrophe can be associated with different types of cell aging, the development of which negatively affects tumor elimination and, consequently, reduces the therapeutic effect. The effective triggering of mitotic catastrophe in clinical practice requires induction of DNA damage as well as inhibition of the molecular pathways that regulate cell cycle arrest and DNA repair. Here we discuss various methods to detect mitotic catastrophe, the mechanisms of its development, and the attempts to use this phenomenon in cancer treatment.
Highlights
Back in 1939, Glücksmann and Spear [1] first described a fraction of cells in the mitotic stage that instantly declined in response to radiation and did not reappear until several hours following treatment
The term mitotic catastrophe to explain the mechanism of cell death linked to delayed mitosis was used for the first time in 1995 [4]
Mitotic catastrophe is considered to be an oncosuppressive mechanism that prevents the survival of cells that are unable to complete mitosis due to defects of the mitotic apparatus, DNA damage, and mitotic checkpoint errors [5, 6]
Summary
Back in 1939, Glücksmann and Spear [1] first described a fraction of cells in the mitotic stage that instantly declined in response to radiation and did not reappear until several hours following treatment. More and more data are accumulating concerning the selective inhibitors of DNA-dependent protein kinases (DNA-PKs), which are involved in the detection of DNA damage and triggering the repair of double-stranded DNA breaks by nonhomologous joining This inhibitor in combination with the PARP inhibitor olaparib, doxorubicin, or radiotherapy causes prolonged arrest of the cell cycle in the G2/M transition, accumulation of micronuclei, and chromosomal aberrations that are indicative of mitotic catastrophe. The selective DNA-PK inhibitor AZD7648 in combination with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, doxorubicin, or radiotherapy has been shown to be efficacious in ovarian and breast cancer cell lines [64] Such combination of drugs causes prolonged arrest of the cell cycle in the G2/M phase, accumulation of micronuclei, and chromosomal aberrations indicative of mitotic catastrophe development. Researchers have recommended various imaging approaches to detect mitotic catastrophe; confocal fluorescence microscopy is recommended to obtain convincing results
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