A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies

Leukemia. 2009 Sep;23(9):1564-76. doi: 10.1038/leu.2009.94. Epub 2009 May 7.

Abstract

Polo-like kinase1 (PLK1) belongs to the family of serine/threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in a variety of human leukemia cell lines (n=20), as well as, freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n=50) and acute lymphoblastic leukemia (n=15) compared with bone marrow mononuclear cells from healthy volunteers (n=13) (acute myelogenous leukemia, P=0.016; acute lymphoblastic leukemia, P=0.008), as measured by real-time RT-PCR. Downregulation of PLK1 by a small interfering RNA in NB4 acute myelogenous leukemia cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound-induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Pre-treatment of cells with the caspase inhibitor Z-VAD-FMK attenuated the action of GW843682X in leukemia cells, indicating the involvement of the caspase pathway in the PLK1 inhibitor-mediated apoptosis. Furthermore, we found that the PLK1 inhibitor synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulin-depolymerizing agent vincristine. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Benzimidazoles / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • G2 Phase / drug effects
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / enzymology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / analysis
  • Thiophenes / pharmacology*
  • Vincristine / pharmacology

Substances

  • 5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-((2-(trifluoromethyl)benzyl)oxy)thiophene-2-carboxamide
  • Benzimidazoles
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Thiophenes
  • Vincristine
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1