A High-Content Small Molecule Screen Identifies Sensitivity of Glioblastoma Stem Cells to Inhibition of Polo-Like Kinase 1
| Autor: | Ana R. Georgian, Jane E. Preston, Patrizia Ferretti, Pär G. Engström, Ding Yu, Ahmed M.O. Elbatsh, Sabine Gogolok, N. Joan Abbott, Stefan H. Stricker, Kin Pong U, Christine Ender, Austin Smith, Patrick J. Paddison, Steven M. Pollard, Sladjana Gagrica, Kevin Harvey, Davide Danovi, Paul Bertone, Amos Folarin |
|---|---|
| Přispěvatelé: | Bertone, Paul [0000-0001-5059-4829], Apollo - University of Cambridge Repository |
| Rok vydání: | 2013 |
| Předmět: |
Swine
medicine.medical_treatment lcsh:Medicine Cell Cycle Proteins Mice 0302 clinical medicine Neural Stem Cells lcsh:Science Cells Cultured Mice Knockout 0303 health sciences Multidisciplinary Brain Neoplasms Reverse Transcriptase Polymerase Chain Reaction Kinase Pteridines Stem-cell therapy Protein-Serine-Threonine Kinases Neural stem cell 3. Good health Cell biology Endothelial stem cell Blood-Brain Barrier 030220 oncology & carcinogenesis Indans Neoplastic Stem Cells Stem cell Research Article Cell Survival Blotting Western Thiophenes Protein Serine-Threonine Kinases Biology PLK1 Small Molecule Libraries 03 medical and health sciences Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Protein Kinase Inhibitors Mitosis 030304 developmental biology lcsh:R Cell Cycle Checkpoints Molecular biology Cell culture Pyrazoles lcsh:Q Benzimidazoles Drug Screening Assays Antitumor Tumor Suppressor Protein p53 Glioblastoma |
| Zdroj: | PLoS ONE PLoS ONE, Vol 8, Iss 10, p e77053 (2013) Danovi, D, Folarin, A, Gogolok, S, Ender, C, Elbatsh, A M O, Engström, P G, Stricker, S H, Gagrica, S, Georgian, A, Yu, D, U, K P, Harvey, K J, Ferretti, P, Paddison, P J, Preston, J E, Abbott, N J, Bertone, P, Smith, A & Pollard, S M 2013, ' A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1 ', PLoS ONE, vol. 8, no. 10, pp. e77053 . https://doi.org/10.1371/journal.pone.0077053 Danovi, D, Folarin, A, Gogolok, S, Ender, C, Elbatsh, A M O, Engström, P G, Stricker, S H, Gagrica, S, Georgian, A, Yu, D, U, K P, Harvey, K J, Ferretti, P, Paddison, P J, Preston, J, Abbott, N J, Bertone, P, Smith, A & Pollard, S M 2013, ' A high-content small molecule screen identifies sensitivity of glioblastoma stem cells to inhibition of polo-like kinase 1 ', PL o S One, vol. 8, no. 10, e77053 . https://doi.org/10.1371/journal.pone.0077053 |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|