Aurora A selective inhibitor MLN8237 suppresses the growth and survival of HTLV-1-infected T-cells in vitro

Cancer Sci. 2010 May;101(5):1204-11. doi: 10.1111/j.1349-7006.2010.01499.x. Epub 2010 Jan 19.

Abstract

Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle. We have shown previously that Aurora A expression is increased aberrantly in human T-cell leukemia virus type 1 (HTLV-1)-infected T-cell lines and primary adult T-cell leukemia cells, and a pan-Aurora kinase inhibitor, which inhibits both Aurora A and Aurora B kinases, reduces viability and induces apoptosis in these cells. However, the specific effects of Aurora A inhibition on HTLV-1-infected T-cells are poorly understood. In this study, we addressed this question by comparing the effects of MLN8237, a selective inhibitor of Aurora A, on cell viability, cell cycle progression, and induction of apoptosis in HTLV-1-infected and -uninfected T-cell lines. MLN8237 reduced the viability of HTLV-1-infected T-cell lines within 24 h, but its effects on that of HTLV-1-uninfected T-cell lines were moderate. MLN8237 induced early apoptosis of HTLV-1-infected T-cell lines without induction of polyploidy. It induced p53 and p21 expression in HTLV-1-infected but not in -uninfected T-cell lines, suggesting that MLN8237-treated HTLV-1-infected T-cell lines exit from mitosis and activate a p53-dependent postmitotic G(1) checkpoint, leading to G(1) arrest followed by the induction of apoptosis. Our results suggest that specific inhibition of Aurora A kinase is a potentially useful therapeutic strategy in the treatment of adult T-cell leukemia and that further in vivo exploration is warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Aurora Kinase B
  • Aurora Kinases
  • Azepines / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / drug therapy*
  • Leukemia-Lymphoma, Adult T-Cell / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyrimidines / pharmacology*
  • T-Lymphocytes / virology*

Substances

  • Azepines
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases