Organotypical vascular model for characterization of radioprotective compounds: Studies on antioxidant 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors

Issue title: Selected Presentations held at the 33th Annual Conference of the German Society for Clinical Microcirculation and Hemorheology, Villingen-Schwenningen, Germany, 14-15 November, 2014

Article type: Research Article

Authors: Ullm, Sandra^; | Laube, Markus^; | Bechmann, Nicole^; | Kniess, Torsten | Pietzsch, Jens^;

Affiliations: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden- Rossendorf, Dresden, Germany | Department of Chemistry and Food Chemistry, Technische Universität Dresden, Dresden, Germany

Note: [] Corresponding author: Jens Pietzsch. Tel.: +49 351 260 2622; Fax: +49 351 260 12622; E-mail: j.pietzsch@hzdr.de

Abstract: 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.

Keywords: Aortic ring model, coxibs, prostanoids, normal tissue damage, radiation therapy, adjuvant radioprotective therapy, cardiovascular disease

DOI: 10.3233/CH-141902

Journal: Clinical Hemorheology and Microcirculation, vol. 58, no. 1, pp. 281-295, 2014