Celecoxib enhances the radiosensitizing effect of 7-hydroxystaurosporine (UCN-01) in human lung cancer cell lines

Young Mee Kim, In Hye Jeong, Hongryull Pyo

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: 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 and Materials: 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.

Original languageEnglish (US)
Pages (from-to)e399-e407
JournalInternational Journal of Radiation Oncology Biology Physics
Volume83
Issue number3
DOIs
StatePublished - Jul 1 2012

Fingerprint

Celecoxib
Radiation-Sensitizing Agents
cultured cells
lungs
Lung Neoplasms
cancer
drugs
Cell Line
inhibitors
ataxia
cytometry
ionizing radiation
upstream
radiation therapy
Pharmaceutical Preparations
tumors
7-hydroxystaurosporine
Ataxia Telangiectasia
proteins
Cyclooxygenase 2 Inhibitors

Keywords

  • COX-2
  • Celecoxib
  • Chk1
  • Radiosensitization
  • UCN-01

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Celecoxib enhances the radiosensitizing effect of 7-hydroxystaurosporine (UCN-01) in human lung cancer cell lines. / Kim, Young Mee; Jeong, In Hye; Pyo, Hongryull.

In: International Journal of Radiation Oncology Biology Physics, Vol. 83, No. 3, 01.07.2012, p. e399-e407.

Research output: Contribution to journalArticle

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abstract = "Purpose: 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 and Materials: 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.",
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