Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated.
OBJECTIVE
Inhibitors of epidermal growth factor receptor (EGFR) have shown dramatic results in a subset of patients with non-small cell lung cancer (NSCLC), and have also been shown to enhance the effect of ionizing radiation (IR). We investigated how gefitinib, an orally given EGFR inhibitor for NSCLC patients, can radiosensitize NSCLC cells.


RESULTS
In clonogenic survival assays performed in three NSCLC cell lines, gefitinib radiosensitized NCI-H460 and VMRC-LCD but not A549 cells. Gefitinib pretreatment induced multinucleated cells after IR exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. Gefitinib also inhibited activation of ataxia telangiectasia mutated (ATM) after IR-exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. An ATM specific inhibitor increased IR-induced multinucleated cells in both NCI-H460 and A549 cells. Gefitinib pretreatment inhibited the gradual decrease of γH2AX foci relative to time after IR exposure in NCI-H460 but not in A549 cells. Suppression of COX-2 in A549 cells induced multinucleated cells and caused radiosensitization after gefitinib+IR treatment. In contrast, COX-2 overexpression in NCI-H460 cells attenuated the induction of multinucleation and radiosensitization after the same treatment.


CONCLUSIONS
Our results suggest that gefitinib radiosensitizes NSCLC cells by inhibiting ATM activity and therefore inducing mitotic cell death, and that COX-2 overexpression in NSCLC cells inhibits this action of gefitinib.
Park
Soo-Yeon
SY
Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea.
Kim
Young Mee
YM
Pyo
Hongryull
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000077156:Gefitinib