Radiosensitivity enhancement by combined treatment of celecoxib and gefitinib on human lung cancer cells.
OBJECTIVE
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.


METHODS
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 G(2) 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 G(2)-M arrest, and combined drug treatment additively attenuated radiation-induced G(2)-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 G(2)-M arrest, possibly via Chk1 and Chk2 inhibition, by the combined drug treatments.
Park
Ji Sun
JS
Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea.
Jun
Hyun Jung
HJ
Cho
Moon Jun
MJ
Cho
Kwan Ho
KH
Lee
Jin Soo
JS
Zo
Jae Ill
JI
Pyo
Hongryull
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D011836:Radiation Tolerance / Q000187:drug effects*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib