An Aurora kinase inhibitor, AMG900, inhibits glioblastoma cell proliferation by disrupting mitotic progression

Cancer Med. 2018 Nov;7(11):5589-5603. doi: 10.1002/cam4.1771. Epub 2018 Sep 17.

Abstract

The Aurora kinase family of serine/threonine protein kinases comprises Aurora A, B, and C and plays an important role in mitotic progression. Several inhibitors of Aurora kinase have been developed as anti-cancer therapeutics. Here, we examined the effects of a pan-Aurora kinase inhibitor, AMG900, against glioblastoma cells. AMG900 inhibited proliferation of A172, U-87MG, and U-118MG glioblastoma cells by upregulating p53 and p21 and subsequently inducing cell cycle arrest and senescence. Abnormal cell cycle progression was triggered by dysregulated mitosis. Mitosis was prolonged due to a defect in mitotic spindle assembly. Despite the presence of an unattached kinetochore, BubR1, a component of the spindle assembly checkpoint, was not recruited. In addition, Aurora B was not recruited to central spindle at anaphase. Abnormal mitotic progression resulted in accumulation of multinuclei and micronuclei, a type of chromosome missegregation, and ultimately inhibited cell survival. Therefore, the data suggest that AMG900-mediated inhibition of Aurora kinase is a potential anti-cancer therapy for glioblastoma.

Keywords: AMG900; Aurora kinase; anti-cancer drug; glioblastoma; mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinases / antagonists & inhibitors
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Humans
  • Mitosis / drug effects
  • Phthalazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
  • Phthalazines
  • Protein Kinase Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Aurora Kinases