Small-molecule inhibition of Aurora kinases triggers spindle checkpoint-independent apoptosis in cancer cells

Biochem Pharmacol. 2008 Mar 1;75(5):1027-34. doi: 10.1016/j.bcp.2007.11.007. Epub 2007 Nov 22.

Abstract

Aurora kinases are key regulators of mitotic progression and have also been implicated in tumorigenesis. Small molecules that inhibit Aurora kinases have shown impressive anticancer activity in preclinical studies and are currently under clinical evaluation. In this study, our data show that suppression of Aurora activity with a specific inhibitor prevents the proliferation of breast cancer cells. Molecular modeling studies indicate that the Aurora inhibitor suppresses Aurora activity by competitive displacement of ATP. Mechanistically, the Aurora inhibitor causes the accumulation of multinucleated cells, leading to profound apoptosis in the absence of caspase-3 activity. Further studies show that the sensitivity of cancer cells to the Aurora inhibitor is independent of the spindle checkpoint. In addition, the Aurora inhibitor acts synergistically with the vinca alkaloids but not with the taxanes in inhibiting cell proliferation and inducing apoptosis. These results suggest that Aurora inhibitors might be effective in spindle checkpoint-defective cancer cells and a combination of Aurora inhibitors with the vinca alkaloids is a promising approach for cancer chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Aurora Kinases
  • Calcium-Binding Proteins / genetics
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Mad2 Proteins
  • Models, Molecular
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Quinazolines / pharmacology*
  • RNA, Small Interfering / genetics
  • Repressor Proteins / genetics
  • Spindle Apparatus
  • Vinblastine / pharmacology

Substances

  • Antineoplastic Agents
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • RNA, Small Interfering
  • Repressor Proteins
  • Vinblastine
  • Aurora Kinases
  • Bub1 spindle checkpoint protein
  • Protein-Serine-Threonine Kinases