Transient treatment with CDK inhibitors eliminates proliferative potential even when their abilities to evoke apoptosis and DNA damage are blocked
| Autor: | Sarah Denny, Andrew Cansfield, Philip Stephen Jackson, Jonathan D. Moore, Douglas S. Williamson, Peter Kierstan, Lan-Zhen Wang, Simon F. Scrace, Joanne Wayne, Andrea M. Lockie, Nicola J. Curtin, Carol Bentley, David R. Newell, Jenifer Borgognoni |
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| Rok vydání: | 2008 |
| Předmět: |
Programmed cell death
DNA damage Antineoplastic Agents Apoptosis X-Linked Inhibitor of Apoptosis Protein Biology Cyclin-dependent kinase Cell Line Tumor Humans CHEK1 RNA Small Interfering Molecular Biology Oxazoles Protein Kinase Inhibitors Cell Proliferation Cell growth Cell Biology Cyclin-Dependent Kinases XIAP Cell biology Thiazoles Pyrimidines Proto-Oncogene Proteins c-bcl-2 Cancer cell Checkpoint Kinase 1 biology.protein Cancer research Myeloid Cell Leukemia Sequence 1 Protein Pyrazoles biological phenomena cell phenomena and immunity Restriction point Protein Kinases Developmental Biology DNA Damage |
| Zdroj: | Cell cycle (Georgetown, Tex.). 7(24) |
| ISSN: | 1551-4005 |
| Popis: | Transient treatment with small molecule CDK inhibitors is toxic to cancer cells and leads to depletion of anti-apoptotic proteins and Chk1, coupled with DNA damage and induction of apoptosis. Here we have examined, which of these phenomena are necessary for CDK inhibitors to have an anti-proliferative effect. We find that 24 hours treatment with either a primarily CDK2-specific, or a primarily CDK7/9-specific, antagonist eliminates proliferative potential even if apoptosis is blocked and the tendency of CDK inhibition to result in DNA damage is overcome by expression of recombinant Chk1. Loss of proliferative potential is correlated with irreversible suppression of biomarkers of cell cycle progression. CDK inhibitors dramatically reduced levels of the anti-apoptotic proteins, Mcl-1 and XIAP, but siRNA-mediated suppression of Mcl-1 and XIAP did not induce cell death in the osteosarcoma cells used in this study. Finally, we found that many literature CDK inhibitors do not effectively suppress the CDK/cyclin complexes responsible for cell cycle progression at the minimum doses required to block proliferation: some are only effective after a substantial delay and may act via inhibition of CDK7. |
| Databáze: | OpenAIRE |
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