title: Celecoxib enhances the radiosensitizing effect of 7-hydroxystaurosporine (UCN-01) in human lung cancer cell lines.
abstract: OBJECTIVE
  7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01.
  
  
  METHODS
  The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using median drug effect analysis and drug-independent action model analysis.
  
  
  RESULTS
  The combination of UCN-01 and celecoxib could induce synergistic cytotoxicity and radiosensitizing effects in in vitro and in vivo systems. The combination of both drugs also cooperatively inhibited IR-induced G(2)/M arrest, and increased the G(2) to mitotic transition.
  
  
  CONCLUSIONS
  Combined treatment with UCN-01 and celecoxib can exert synergistically enhanced radiosensitizing effects via cooperative inhibition of the ionizing radiation-activated G(2) checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.
authors.affiliation: Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Jeong
authors.forename: Hongryull
authors.initials: H
authors.lastname: Pyo
mesh_terms: D000068579:Celecoxib; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D019311:Staurosporine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019311:Staurosporine; D000068579:Celecoxib