title: Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells.
abstract: BACKGROUND
  During metaphase clathrin stabilises the mitotic spindle kinetochore (K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis.
  
  
  RESULTS
  Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition.
  
  
  CONCLUSIONS
  Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.
authors: Children's Medical Research Institute, The University of Sydney, 214 Hawkesbury Road, Westmead, NSW, 2145, Australia.
authors: Charlotte M
authors: CM
authors: Smith
authors: Volker
authors: V
authors: Haucke
authors: Adam
authors: A
authors: McCluskey
authors: Phillip J
authors: PJ
authors: Robinson
authors: Megan
authors: M
authors: Chircop
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002502:Centrioles / Q000378:metabolism; D002966:Clathrin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D008941:Spindle Apparatus / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002966:Clathrin; D013449:Sulfonamides; D053778:Thiazolidines; C578512:pitstop 2