Ullm Sandra, Laube Markus, Bechmann Nicole, Kniess Torsten, Pietzsch Jens
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany.
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany.
Clin Hemorheol Microcirc. 2014;58(1):281-95. doi: 10.3233/CH-141902.
Radiotherapy of various cancers is closely associated with increased cardiovascular morbidity and mortality. Arachidonic acid metabolites are supposed to play a key role in radiation-induced vascular dysfunction. This study was designed to evaluate the effects of novel, antioxidative 2,3-diaryl-substituted indole-based selective cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) on radiation-induced formation of arachidonic acid metabolites via COX-2 and oxidant stress pathways in an organotypical vascular model of rat aortic rings. Acute and subacute effects of X-ray radiation (4 and 10 Gy; 1 and 3 days post irradiation) with or without the presence of 1 μM of the 2,3-diaryl-indole coxib 2-[4-(aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-1H-indole (C1) or celecoxib as reference compared to sham-irradiated controls were assessed. The following parameters were measured: metabolic activity of the aortic rings; induction and regulation of COX-2 expression; release of prostaglandin E2 and F2α-isoprostane. Irradiation without presence of coxibs resulted in a dose-dependent augmentation of all parameters studied. When aortic rings were exposed to the 2,3-diaryl-indole coxib 1 h before irradiation, metabolic activity was restored and the release of both prostaglandin and isoprostane was inhibited. The latter indicates a direct interaction with oxidant stress pathways. By contrast, celecoxib exhibited only slight effects on the formation of isoprostane. The reduction of radiation-induced vascular dysfunction by antioxidative coxibs may widen the therapeutic window of COX-2 targeted treatment.
各种癌症的放射治疗与心血管疾病发病率和死亡率的增加密切相关。花生四烯酸代谢产物被认为在辐射诱导的血管功能障碍中起关键作用。本研究旨在评估新型抗氧化2,3-二芳基取代的吲哚基选择性环氧化酶-2（COX-2）抑制剂（2,3-二芳基吲哚类coxibs）在大鼠主动脉环器官型血管模型中通过COX-2和氧化应激途径对辐射诱导的花生四烯酸代谢产物形成的影响。评估了X射线辐射（4和10 Gy；照射后1天和3天）在有或没有1 μM 2,3-二芳基吲哚类coxib 2-[4-(氨磺酰基)phenyl]-3-(4-甲氧基苯基)-1H-吲哚（C1）或塞来昔布作为对照的情况下与假照射对照组相比的急性和亚急性效应。测量了以下参数：主动脉环的代谢活性；COX-2表达的诱导和调节；前列腺素E2和F2α-异前列腺素的释放。在没有coxibs的情况下进行辐射导致所有研究参数呈剂量依赖性增加。当主动脉环在照射前1小时暴露于2,3-二芳基吲哚类coxib时，代谢活性恢复，前列腺素和异前列腺素的释放均受到抑制。后者表明与氧化应激途径有直接相互作用。相比之下，塞来昔布对异前列腺素的形成仅表现出轻微影响。抗氧化coxibs减少辐射诱导的血管功能障碍可能会拓宽COX-2靶向治疗的治疗窗口。
