DNA-PKcs-dependent modulation of cellular radiosensitivity by a selective cyclooxygenase-2 inhibitor.
OBJECTIVE
Inhibition of cyclooxygenase-2 has been shown to increase radiosensitivity. Recently, the suppression of radiation-induced DNA-dependant protein kinase (DNA-PK) activity by the selective cyclooxygenase-2 inhibitor celecoxib was reported. Given the importance of DNA-PK for repair of radiation-induced DNA double-strand breaks by nonhomologous end-joining and the clinical use of the substance, we investigated the relevance of the DNA-PK catalytic subunit (DNA-PKcs) for the modulation of cellular radiosensitivity by celecoxib.


METHODS
We used a syngeneic model of Chinese hamster ovarian cell lines: AA8, possessing a wild-type DNK-PKcs; V3, lacking a functional DNA-PKcs; and V3/WT11, V3 stably transfected with the DNA-PKcs. The cells were treated with celecoxib (50 muM) for 24 h before irradiation. The modulation of radiosensitivity was determined using the colony formation assay.


RESULTS
Treatment with celecoxib increased the cellular radiosensitivity in the DNA-PKcs-deficient cell line V3 with a dose-enhancement ratio of 1.3 for a surviving fraction of 0.5. In contrast, clonogenic survival was increased in DNA-PKcs wild-type-expressing AA8 cells and in V3 cells transfected with DNA-PKcs (V3/WT11). The decrease in radiosensitivity was comparable to the radiosensitization in V3 cells, with a dose-enhancement ratio of 0.76 (AA8) and 0.80 (V3/WT11) for a survival of 0.5.


CONCLUSIONS
We have demonstrated a DNA-PKcs-dependent differential modulation of cellular radiosensitivity by celecoxib. These effects might be attributed to alterations in signaling cascades downstream of DNA-PK toward cell survival. These findings offer an explanation for the poor outcomes in some recently published clinical trials.
Kodym
Elisabeth
E
Department of Radiation Oncology, Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
Kodym
Reinhard
R
Chen
Benjamin P
BP
Chen
David J
DJ
Morotomi-Yano
Keiko
K
Choy
Hak
H
Saha
Debabrata
D
D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D000068579:Celecoxib; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D003412:Cricetulus; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D004247:DNA; D051747:DNA-Activated Protein Kinase; D000068579:Celecoxib