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Palbociclib Effectively Halts Proliferation but Fails to Induce Senescence in Patient-Derived Glioma Stem Cells.
- Source :
-
Molecular neurobiology [Mol Neurobiol] 2019 Nov; Vol. 56 (11), pp. 7810-7821. Date of Electronic Publication: 2019 May 23. - Publication Year :
- 2019
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Abstract
- Glioblastoma multiforme is the most aggressive primary brain tumor. Current knowledge suggests that the growth and recurrence of these tumors are due in part to the therapy-resistant glioma stem cell subpopulation, which possesses the ability for self-renewal and proliferation, driving tumor progression. In many cancers, the p16 <superscript>INK4a</superscript> -CDK4/6-pRb pathway is disrupted in favor of cell cycle progression. In particular, the frequent deregulation of CDK4/6 in cancer positions these kinases as promising targets. Palbociclib, a potent and selective CDK4/6 inhibitor, has been approved by the FDA as a first-line treatment of advanced breast cancer and there is currently interest in evaluating its effect on other cancer types. Palbociclib has been reported to be efficient, not only at halting proliferation, but also at inducing senescence in different tumor types. In this study, we evaluated the effect of this inhibitor on four patient-derived glioma stem cell-enriched cell lines. We found that Palbociclib rapidly and effectively inhibits proliferation without affecting cell viability. We also established that in these cell lines CDK6 is the key interphase CDK for controlling cell cycle progression. Prolonged exposure to Palbociclib induced a senescent-like phenotype characterized by flattened morphology, cell cycle arrest, increased β-galactosidase activity and induction of other senescent-associated markers. However, we found that after Palbociclib removal cell lines resumed normal proliferation, which implies they conserved their replicative potential. As a whole, our results indicate that in patient-derived glioma stem cell-enriched cell lines, Palbociclib induces a senescent-like quiescence rather than true senescence.
- Subjects :
- Apoptosis drug effects
Brain Neoplasms metabolism
Cell Cycle Checkpoints drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Cyclin-Dependent Kinase 4 antagonists & inhibitors
Cyclin-Dependent Kinase 4 metabolism
Cyclin-Dependent Kinase 6 antagonists & inhibitors
Cyclin-Dependent Kinase 6 metabolism
Fibroblasts drug effects
Fibroblasts metabolism
Glioma metabolism
Humans
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
Phenotype
Roscovitine pharmacology
Brain Neoplasms pathology
Cellular Senescence drug effects
Glioma pathology
Neoplastic Stem Cells pathology
Piperazines pharmacology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1182
- Volume :
- 56
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 31124078
- Full Text :
- https://doi.org/10.1007/s12035-019-1633-z