title: Anaphase catastrophe is a target for cancer therapy.
abstract: Neoplastic cells are genetically unstable. Strategies that target pathways affecting genome instability can be exploited to disrupt tumor cell growth, potentially with limited consequences to normal cells. Chromosomal instability (CIN) is one type of genome instability characterized by mitotic defects that increase the rate of chromosome mis-segregation. CIN is frequently caused by extra centrosomes that transiently disrupt normal bipolar spindle geometry needed for accurate chromosome segregation. Tumor cells survive with extra centrosomes because of biochemical pathways that cluster centrosomes and promote chromosome segregation on bipolar spindles. Recent work shows that targeted inhibition of these pathways prevents centrosome clustering and forces chromosomes to segregate to multiple daughter cells, an event triggering apoptosis that we refer to as anaphase catastrophe. Anaphase catastrophe specifically kills tumor cells with more than 2 centrosomes. This death program can occur after genetic or pharmacologic inhibition of cyclin dependent kinase 2 (Cdk2) and is augmented by combined treatment with a microtubule inhibitor. This proapoptotic effect occurs despite the presence of ras mutations in cancer cells. Anaphase catastrophe is a previously unrecognized mechanism that can be pharmacologically induced for apoptotic death of cancer cells and is, therefore, appealing to engage for cancer therapy and prevention.
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Galimberti
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Thompson
authors.forename: Saranya
authors.initials: S
authors.lastname: Ravi
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000705:Anaphase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018385:Centrosome / Q000648:ultrastructure; D043171:Chromosomal Instability; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D006801:Humans; D008495:Medical Oncology / Q000379:methods; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018631:ras Proteins