Polo-like kinase 1 inhibition causes decreased proliferation by cell cycle arrest, leading to cell death in glioblastoma

Cancer Gene Ther. 2013 Sep;20(9):499-506. doi: 10.1038/cgt.2013.46. Epub 2013 Jul 26.

Abstract

Glioblastoma (GBM) is one of the most aggressive central nervous system tumors with a patient's median survival of <1 year. Polo-like kinases (PLKs) are a family of serine/threonine kinases that have key roles in cell cycle control and DNA-damage response. We evaluated PLK1, 2, 3 and 4 gene expression in 8 GBM cell lines and 17 tumor samples, and analyzed the effect of the PLK1 inhibition on SF188 and T98G GBM cell lines and 13 primary cultures. Our data showed PLK1 overexpression and a variable altered expression of PLK2, 3 and 4 genes in GBM tumor samples and cell lines. Treatments with nanomolar concentrations of BI 2536, BI 6727, GW843682X or GSK461364 caused a significant decrease in GBM cells proliferation. Colony formation was also found to be inhibited (P<0.05), whereas apoptosis rate and mitotic index were significantly increased (P<0.05) after PLK1 inhibition in both GBM cell lines. Cell cycle analysis showed an arrest at G2 (P<0.05) and cell invasion was also decreased after PLK1 inhibition. Furthermore, simultaneous combinations of BI 2536 and temozolomide produced synergistic effects for both the cell lines after 48 h of treatment. Our findings suggest that PLK1 might be a promising target for the treatment of GBMs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Cycle Checkpoints* / drug effects
  • Cell Cycle Checkpoints* / genetics
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / genetics
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Drug Synergism
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Temozolomide
  • Tumor Stem Cell Assay

Substances

  • Antineoplastic Agents, Alkylating
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Dacarbazine
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Temozolomide