The mitotic checkpoint in cancer therapy.
The mitotic checkpoint is a key cell cycle control mechanism that ensures an accurate segregation of chromosomes during mitosis by delaying the onset of anaphase until all chromosomes are properly attached to a bipolar mitotic spindle. While complete loss of this checkpoint is lethal in vertebrates, a weakened mitotic checkpoint is frequently seen in cancer cells and it may contribute to tumorigenesis. Many anti-tumor drugs, including spindle assembly inhibitors and DNA damaging agents, can activate the mitotic checkpoint. However, since these drugs influence interphase events besides activating the mitotic checkpoint, the role of the mitotic checkpoint in drug-induced cell death remained unclear. Using a KSP antagonist that specifically acts on mitotic cells, we have recently shown that activation of the mitotic checkpoint followed by mitotic slippage or adaptation, activates Bax and initiates apoptosis. Notably, cells with a weakened mitotic checkpoint incur much less apoptotic death than their checkpoint-proficient counterparts, indicating the requirement of a competent mitotic checkpoint in the induction of apoptosis. In light of these findings and other recent reports, the potential influence of the mitotic checkpoint in response to chemotherapies, and the strategy to target the mitotic checkpoint for cancer therapeutics are discussed.
Tao
Weikang
W
Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
D000818:Animals; D050256:Antimitotic Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*
D050256:Antimitotic Agents; D000970:Antineoplastic Agents