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Radiosensitivity Enhancement by Combined Treatment of Celecoxib and Gefitinib on Human Lung Cancer Cells

Authors' Affiliations: ¹ Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea and ² Department of Therapeutic Radiology, Chungnam National University, Taejon, Korea

Requests for reprints: Hongryull Pyo, Research Institute and Hospital, National Cancer Center, 809 Madu-1-dong, ILsan-gu, Goyang-si, Gyeonggi-do, Korea. Phone: 82-31-920-1723; Fax: 82-31-920-0149; E-mail: quasar93{at}ncc.re.kr.

Purpose: To characterize the radiation-enhancing effects and underlying mechanisms of combined treatment with celecoxib, a cyclooxygenase-2 selective inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in human lung cancer cells.

Experimental Design: Clonogenic cytotoxicity assays and clonogenic radiation survival assays after treatments with celecoxib and gefitinib with or without radiation were done on three human lung cancer cell lines. Synergisms after combined treatment with celecoxib, gefitinib, and radiation were investigated using isobologram and statistical analyses according to an independent action model. Alterations in apoptosis and cell cycle were measured to identify the mechanisms underlying the cell killing or radiation-enhancing effects of celecoxib and gefitinib combination treatment. Western blots for phosphorylated EGFR, EGFR, cyclooxygenase-2, and G₂ checkpoint molecules were conducted after treatment with celecoxib and/or gefitinib with or without radiation.

Results: Combination celecoxib, gefitinib, and radiation treatments were shown to be synergistic in causing clonogenic cell deaths in all cell lines tested, but the nature of synergism was cell type specific. The combined drug treatments induced apoptosis in an additive manner in A549 cells and in a synergistic manner in NCI-H460 and VMRC-LCD cells. Celecoxib or gefitinib attenuated radiation-induced G₂-M arrest, and combined drug treatment additively attenuated radiation-induced G₂-M arrest in all cell lines. Radiation-induced checkpoint kinase (Chk) 1 and Chk2 phosphorylation were inhibited by celecoxib and gefitinib treatment, respectively.

Conclusions: Combined celecoxib and gefitinib treatments were shown to synergistically enhance the effect of radiation on lung cancer cells. The mechanisms underlying these synergistic effects seem to involve the synergistic enhancement of apoptosis and cooperative attenuation of radiation-induced G₂-M arrest, possibly via Chk1 and Chk2 inhibition, by the combined drug treatments.

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