title: Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors.
abstract: 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.
authors: Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Ju-Hee
authors: JH
authors: Lee
authors: Megan L
authors: ML
authors: Choy
authors: Lang
authors: L
authors: Ngo
authors: Gisela
authors: G
authors: Venta-Perez
authors: Paul A
authors: PA
authors: Marks
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004351:Drug Resistance; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; C518919:CHIR-124; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011804:Quinolines; D011812:Quinuclidines; D013876:Thiophenes; D000077337:Vorinostat; C054852:7-hydroxystaurosporine; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D019311:Staurosporine