title: Relationship between epidermal growth factor receptor (EGFR) mutation and serum cyclooxygenase-2 Level, and the synergistic effect of celecoxib and gefitinib on EGFR expression in non-small cell lung cancer cells.
abstract: Epidermal growth factor receptor (EGFR) mutations occur mostly in patients with lung adenocarcinoma; such patients are also more likely to express cyclooxygenase-2 (COX-2), indicating a possible relationship between EGFR mutation and COX-2. The COX-2 and EGFR pathways mutually enhance their procarcinogenic effects in different tumor types. Therefore, simultaneous EGFR and COX-2 inhibition may be a promising therapeutic approach for patients with lung adenocarcinoma. We obtained tissue and serum samples from patients with non-small cell lung cancer (NSCLC) to detect the relationship between EGFR mutation and serum COX-2 level. Subsequently, gefitinib was combined with celecoxib to investigate the efficacy of inhibition in vitro in two NSCLC cell lines: HCC827 (del E746-A750) and A549 (wild-type EGFR). The cells were treated with gefitinib or celecoxib alone or with gefitinib plus celecoxib. Cell proliferation and apoptosis were assessed and correlated with expression of COX-2 and phosphorylated (p)-EGFR. The EGFR mutation rate of the high-COX-2 patients was significantly higher than that in the low-COX-2 patients. Multivariate analysis showed that high COX-2 levels were independently associated with EGFR mutation. Celecoxib and gefitinib inhibited cell growth in both cell lines. At sufficiently high concentrations, celecoxib plus gefitinib significantly mutually enhanced their anti-proliferative and apoptotic effects in both cell lines. At low concentrations, the combination had no additional effects on A549 cells. There was increased down regulation of COX-2 and p-EGFR when both cell lines were treated with high-concentration celecoxib plus gefitinib compared to either agent alone. This study demonstrates that high serum COX-2 levels may indicate EGFR mutations and that the efficacy of combined celecoxib and gefitinib is significantly greater in NSCLC cells with EGFR mutations; at high concentrations, the combination is efficacious in wild-type NSCLC cells.
authors.affiliation: Department of Oncology, Shihezi University School of Medicine, The First Affiliated Hospital Shihezi 832000, Xinjiang, P. R. China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Anyang Tumor Hospital Anyang, Henan, People's Republic of China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Oncology, Shihezi University School of Medicine, The First Affiliated Hospital Shihezi 832000, Xinjiang, P. R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Oncology, Shihezi University School of Medicine, The First Affiliated Hospital Shihezi 832000, Xinjiang, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Shihezi University School of Medicine, The First Affiliated Hospital Shihezi 832000, Xinjiang, P. R. China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Oncology, Shihezi University School of Medicine, The First Affiliated Hospital Shihezi 832000, Xinjiang, P. R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000068579:Celecoxib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000097:blood*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011799:Quinazolines; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib
keywords: EGFR; Non-small cell lung cancer; cyclooxygenase-2; epidermal growth factor receptor mutation