Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults and there are few effective treatments. GBMs contain cells with molecular and cellular characteristics of neural stem cells that drive tumour growth. Here we compare responses of human glioblastoma-derived neural stem (GNS) cells and genetically normal neural stem (NS) cells to a panel of 160 small molecule kinase inhibitors. We used live-cell imaging and high content image analysis tools and identified JNJ-10198409 (J101) as an agent that induces mitotic arrest at prometaphase in GNS cells but not NS cells. Antibody microarrays and kinase profiling suggested that J101 responses are triggered by suppression of the active phosphorylated form of polo-like kinase 1 (Plk1) (phospho T210), with resultant spindle defects and arrest at prometaphase. We found that potent and specific Plk1 inhibitors already in clinical development (BI 2536, BI 6727 and GSK 461364) phenocopied J101 and were selective against GNS cells. Using a porcine brain endothelial cell blood-brain barrier model we also observed that these compounds exhibited greater blood-brain barrier permeability in vitro than J101. Our analysis of mouse mutant NS cells (INK4a/ARF(-/-), or p53(-/-)), as well as the acute genetic deletion of p53 from a conditional p53 floxed NS cell line, suggests that the sensitivity of GNS cells to BI 2536 or J101 may be explained by the lack of a p53-mediated compensatory pathway. Together these data indicate that GBM stem cells are acutely susceptible to proliferative disruption by Plk1 inhibitors and that such agents may have immediate therapeutic value.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / pharmacology
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism
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Blotting, Western
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cells, Cultured
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Drug Screening Assays, Antitumor / methods
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Glioblastoma / enzymology
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Glioblastoma / genetics
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Glioblastoma / pathology
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Humans
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Indans / pharmacology
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Mice
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Mice, Knockout
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / pathology
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Neural Stem Cells / drug effects*
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Neural Stem Cells / enzymology
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Neural Stem Cells / pathology
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pteridines / pharmacology
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Pyrazoles / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Small Molecule Libraries / pharmacology*
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Swine
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Thiophenes / pharmacology
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
Substances
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(6,7-dimethoxy-2,4-dihydroindeno(1,2-c)pyrazol-3-yl)(3-fluorophenyl)amine
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BI 2536
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BI 6727
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Benzimidazoles
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Cell Cycle Proteins
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GSK 461364
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Indans
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pteridines
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Pyrazoles
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Small Molecule Libraries
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Thiophenes
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Tumor Suppressor Protein p53
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Protein Serine-Threonine Kinases