title: Combined Inhibition of Epidermal Growth Factor Receptor and Cyclooxygenase-2 as a Novel Approach to Enhance Radiotherapy.
abstract: Targeting epidermal growth factor receptor (EGFR) is a promising approach to increasing radiosensitivity of head and neck cancers but treatment resistance remains an important clinical problem. We hypothesize that combined EGFR and cyclooxygenase-2 (COX-2) inhibition, using small molecule inhibitors erlotinib and celecoxib, respectively would further increase the antitumor activity of radiotherapy. The effects of combinations of celecoxib, erlotinib and ionizing radiation (IR) on cell growth, cell cycle progression and apoptosis of head and neck cancer cell lines were assessedin vitroby cell viability, clonogenic survival, flow cytometry and Annexin V assays andin vivo. The effects of celecoxib, erlotinib and IR on primary and downstream molecular targets were analyzed by immunoblotting & ELISA assays. Compared to single or double agent approaches, concurrent celecoxib, erlotinib and IR was the most effective regimen at reducing clonogenic survival, increasing apoptosis and inhibiting tumor growthin vivo. Concurrent treatment with celecoxib and erlotinib ± IR inhibited multiple prosurvival proteins including p-ERK1/2, p-EGFR, p-AKT, p-STAT3, COX-2 and PGE-2. The combination of celecoxib, erlotinib and IR is a promising strategy to overcoming resistance to combined EGFR inhibition and IR alone.
authors.affiliation: Department of Radiation Oncology, Mount Sinai School of Medicine, New York ; Department of Hematology and Oncology, First hospital, Jilin University, Changchun, China.
authors.forename: Shibo
authors.initials: S
authors.lastname: Fu
authors.forename: Michael
authors.initials: M
authors.lastname: Rivera
authors.forename: Eric C
authors.initials: EC
authors.lastname: Ko
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.forename: Chien-Ting
authors.initials: CT
authors.lastname: Chen
authors.forename: Ha Linh
authors.initials: HL
authors.lastname: Vu
authors.forename: David
authors.initials: D
authors.lastname: Cannan
authors.forename: Samuel
authors.initials: S
authors.lastname: Eisenstein
authors.forename: Barry S
authors.initials: BS
authors.lastname: Rosenstein
authors.forename: Julio
authors.initials: J
authors.lastname: Aguirre-Ghiso
authors.forename: Shu-Hsia
authors.initials: SH
authors.lastname: Chen
authors.forename: Johnny
authors.initials: J
authors.lastname: Kao
keywords: Celecoxib; Cyclooxygenase-2; Epidermal growth factor receptor; Erlotinib; Head and neck cancer; Ionizing radiation