Role of checkpoint kinase 1 (Chk1) in the mechanisms of resistance to histone deacetylase inhibitors Journal Article

   


Authors: Lee, J. H.; Choy, M. L.; Ngo, L.; Venta-Perez, G.; Marks, P. A.
Article 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 HDACiinduced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity.
Keywords: unclassified drug; human cell; histone deacetylase inhibitor; drug activity; nonhuman; protein function; sensitivity analysis; mitosis; chromosome; mouse; animals; mice; cell death; dna damage; cell survival; cells, cultured; spleen; protein kinases; animal experiment; rna interference; antineoplastic activity; drug resistance; enzyme activity; cell line, tumor; chromatid; chromosome aberration; nucleotide sequence; immunoblotting; vorinostat; histone deacetylase inhibitors; hydroxamic acids; fibroblasts; checkpoint kinase 2; cell cycle g2 phase; checkpoint kinase 1; histones; romidepsin; histone deacetylases; phosphotransferase inhibitor; urea; quinolines; azd 7762; thiophenes; foreskin; entinostat; staurosporine; quinuclidines; 7 hydroxystaurosporine; chir 124; ?h2ax
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 108
Issue: 49
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2011-12-06
Start Page: 19629
End Page: 19634
Language: English
DOI: 10.1073/pnas.1117544108
PROVIDER: scopus
PMCID: PMC3241758
PUBMED: 22106282
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-83755195245&partnerID=40&md5=db047220430f58bf00e413d8c29f98fc
Notes: --- - "Export Date: 1 February 2012" - "CODEN: PNASA" - "Source: Scopus"
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MSK Authors
  1. Lang Ngo
    27 Ngo
  2. Gisela Venta-Perez
    23 Venta-Perez
  3. Ju-Hee Lee
    9 Lee
  4. Megan Lee Choy
    6 Choy
  5. Paul Marks
    186 Marks
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