Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated

Molecular Cancer

Research

Soo-Yeon Park¹  Young Mee Kim¹  Hongryull Pyo¹ 

[1] Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, 135-710, Seoul, Republic of Korea;Research Institute and Hospital, National Cancer Center, 809 Madu-1-dong, ILsandong-gu, Goyang, 410-769, Gyeonggi, Republic of Korea;

关键词: Epidermal Growth Factor Receptor;    A549 Cell;    Cetuximab;    Gefitinib;    Ionize Radiation;   

DOI  :  10.1186/1476-4598-9-222

 received in 2009-08-18, accepted in 2010-08-23,  发布年份 2010

来源: Springer

【 摘 要 】

PurposeInhibitors 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.Experimental Design and ResultsIn 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Park et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.