Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage

Cancer Cell. 2010 Oct 19;18(4):382-95. doi: 10.1016/j.ccr.2010.08.010.


Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindle assembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to the APC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase without perturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest induced by a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is required to inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positive feedback loop that amplifies the ability of TAME to induce mitotic arrest.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • Metaphase / drug effects
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Mitosis / drug effects*
  • Mutant Proteins / metabolism
  • Prodrugs / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Binding / drug effects
  • Protein Biosynthesis / drug effects
  • Spindle Apparatus / drug effects*
  • Spindle Apparatus / pathology*
  • Tosylarginine Methyl Ester / pharmacology*
  • Ubiquitin-Protein Ligase Complexes / antagonists & inhibitors*
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Xenopus


  • Enzyme Inhibitors
  • Mutant Proteins
  • Prodrugs
  • Proteasome Inhibitors
  • Tosylarginine Methyl Ester
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Proteasome Endopeptidase Complex