Combined Inhibition of Epidermal Growth Factor Receptor and Cyclooxygenase-2 as a Novel Approach to Enhance Radiotherapy.
Combined Inhibition of Epidermal Growth Factor Receptor and Cyclooxygenase-2 as a Novel Approach to Enhance Radiotherapy.
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DOI：
10.4172/2157-7013.s1-002
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发表时间：
2011-10
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通讯作者：
S. Fu;M. Rivera;E. Ko;A. Sikora;Chien‐Ting Chen;Ha Linh Vu;D. Cannan;S. Eisenstein;B. Rosenstein;J. Aguirre-Ghiso;Shu-Hsia Chen;J. Kao
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作者：
S. Fu;M. Rivera;E. Ko;A. Sikora;Chien‐Ting Chen;Ha Linh Vu;D. Cannan;S. Eisenstein;B. Rosenstein;J. Aguirre-Ghiso;Shu-Hsia Chen;J. Kao
靶向表皮生长因子受体（EGFR）是一种有前途的方法，以增加放射敏感性的头颈部癌症，但治疗耐药性仍然是一个重要的临床问题。我们假设，分别使用小分子抑制剂厄洛替尼和塞来昔布联合抑制EGFR和环氧合酶-2（考克斯-2）将进一步增加放疗的抗肿瘤活性。通过体外细胞活力、克隆形成存活率、流式细胞术和膜联蛋白V测定以及体内试验，评估了塞来昔布、厄洛替尼和电离辐射（IR）联合用药对头颈癌细胞系的细胞生长、细胞周期进展和凋亡的影响。通过免疫印迹和ELISA分析塞来昔布、厄洛替尼和IR对主要和下游分子靶点的影响。与单药或双药治疗方法相比，塞来昔布、厄洛替尼和IR联合治疗在降低体内克隆形成存活率、增加细胞凋亡和抑制肿瘤生长方面是最有效的方案。塞来昔布和厄洛替尼± IR联合治疗可抑制多种促生存蛋白，包括p-ERK 1/2、p-EGFR、p-AKT、p-STAT 3、考克斯-2和PGE-2。塞来昔布、厄洛替尼和IR的组合是克服对EGFR抑制和IR单独组合的抗性的有希望的策略。
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 assessed in vitro by cell viability, clonogenic survival, flow cytometry and Annexin V assays and in 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 growth in 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.