Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors
| Autor: | Gisela Venta-Perez, Paul A. Marks, Ju-Hee Lee, Megan L. Choy, Lang Ngo |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Quinuclidines Cell Survival Foreskin Immunoblotting Drug Resistance Thiophenes Biology Hydroxamic Acids Romidepsin Histones Mice chemistry.chemical_compound Cell Line Tumor medicine Animals Humans Urea CHEK1 Mitosis Vorinostat Cells Cultured Multidisciplinary Entinostat Fibroblasts Biological Sciences G2-M DNA damage checkpoint Staurosporine Molecular biology Histone Deacetylase Inhibitors chemistry Checkpoint Kinase 1 Cancer cell Quinolines Cancer research RNA Interference Histone deacetylase biological phenomena cell phenomena and immunity Protein Kinases Spleen DNA Damage medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 108:19629-19634 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1117544108 |
| Popis: | Histone deacetylase inhibitors (HDACi) are a new group of anticancer drugs with tumor selective toxicity. Normal cells are relatively resistant to HDACi-induced cell death compared with cancer cells. Previously, we found that vorinostat induces DNA breaks in normal and transformed cells, which normal but not cancer cells can repair. In this study, we found that checkpoint kinase 1 (Chk1), a component of the G2 DNA damage checkpoint, is important in the resistance of normal cells to HDACi in vitro and in vivo. Inhibition of Chk1 activity with Chk1 inhibitor (UCN-01, AZD7762, or CHIR-124) in normal cells increases their sensitivity to HDACi (vorinostat, romidepsin, or entinostat) induced cell death, associated with extensive mitotic disruption. Mitotic abnormalities included loss of sister chromatid cohesion and chromosomal disruption. Inhibition of Chk1 did increase HDACi-induced cell death of transformed cells. Thus, Chk1 is an important factor in the resistance of normal cells, and some transformed cells, to HDACi-induced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity. |
| Databáze: | OpenAIRE |
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