PLK1 inhibitor facilitates the suppressing effect of temozolomide on human brain glioma stem cells

J Cell Mol Med. 2018 Nov;22(11):5300-5310. doi: 10.1111/jcmm.13793. Epub 2018 Aug 22.

Abstract

Glioblastoma is the most frequent and most aggressive brain tumour in adults. Temozolomide is an oral chemotherapy drug and one of the major components of chemotherapy regimens used as a treatment of some brain cancers. We examined the tolerance of stem cells isolated from glioma cell line U87 and U251 to temozolomide (TMZ) and explored the effect of PLK1 (Polo like kinase 1) protein expression on TMZ sensibility. In our results, the inhibitory effects of TMZ on glioma cells U87, U251 and its stem cells were confirmed to be dose dependent and time dependent. Compared with glioma cells, the glioma stem cells showed a greater degree of tolerance. As the concentration of TMZ increased, the expression of PLK1 protein increased in U87 cells, CD133+ U87 stem cells and CD133- U87 cells. The increase range of PLK1 protein was large in CD133+ U87 stem cells and small in CD133- U87 cells. TMZ treatment in cells with low PLK1 protein expression efficiently suppressed the cell proliferation and sphere formation, while G2/M arrest was strongly induced. What's more, TMZ and PLK1 inhibitor synergize to inhibit glioma growth in vivo. In conclusion, our results suggest that down-regulation of PLK1 protein enhanced the inhibition of TMZ on glioma stem cells, suggesting its clinical value to adverse TMZ resistance in glioma treatment.

Keywords: PLK1; BI2536; glioma stem cells; temozolomide.

MeSH terms

  • AC133 Antigen / genetics
  • Apoptosis / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Temozolomide / pharmacology*

Substances

  • AC133 Antigen
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Temozolomide