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

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 M of the 2,3-diaryl-indole coxib 2-[4-(aminosulfonyl)phenyl]-3-(4methoxyphenyl)-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 E 2 and F 2␣ -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.

Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy—A Hypothesis-Driven Review

“…However, with respect to the clinical situation the development and evaluation of novel drug candidates or new strategies is of urgent need. Our own investigations provided experimental evidence on 2,3-diaryl-substituted indole-based COX-2 inhibitors exerting at pharmacologically low concentration levels antioxidant activity, for instance by scavenging • OH and O 2 •− thus protecting low density lipoproteins from oxidative damage as well as demonstrating radioprotection on both cellular and organotypical vascular models [ 30 , 31 ]. From these data we deduced the hypothesis that antioxidant COX-2 inhibitors can be considered to act as a double-edged sword by intervening in the immediate and also delayed responses to ionizing radiation.…”

“…We have performed radioprotection studies with the sulfonyl-containing 2,3-diaryl-substituted indole RIVAD018 and observed an effect both in cellular and organotypical vascular models [ 30 , 31 ]. The 2,3-diaryl-substituted indoles have been initially developed by Hu and Guo et al as potent COX-2 selective inhibitors [ 136 , 137 , 138 ].…”

“…The anti-inflammatory and antioxidant intervention in these autocrine and paracrine activation loops of the vascular endothelial cells suggest that antioxidant COX-2 inhibitors may act as radioprotectors to reduce radiation-induced vascular dysfunction [ 135 , 145 ]. With the aim to evaluate the radioprotective effects of 2,3-diarylindoles in an organotypical vascular system, RIVAD018 was furthermore evaluated in a rat aortic ring model [ 30 , 146 ]. For that, rat aortas obtained from male Wistar Unilever rats were dissected in small rings and irradiated using moderate doses (sham, 4 and 10 Gy) of X-ray radiation in the presence of 1 µM RIVAD018 and celecoxib, respectively.…”

“…Celecoxib was only effective to inhibit PGE 2 formation but not to decrease 8-iso-15(R)-PGF 2α levels. In contrast to celecoxib, RIVAD018 was able to block PGE 2 as well as 8-iso-15(R)-PGF 2α formation [ 30 , 146 ]. In this context, F 2α -isoprostanes deriving from non-enzymatic oxidation processes were shown to act as reliable markers of in vivo oxidative stress [ 55 , 148 ].…”

Enzyme controlled release of celecoxib from inulin based nanomicelles

“…It is an NSAID that inhibits cyclooxygenase (COX), the enzyme responsible for conversion of arachidonic acid to prostaglandins. In particular, CLX belong to the class of Coxib, the non-steroidal anti-inflammatory drugs that, unlike most NSAIDs, are selective for inhibiting COX-2, the induced isoform of the two existing COX [5], which is almost absent in normal healthy tissues and cells but it increase during inflammation process, induced by various proinflammatory, catabolic and stress mediators such as cytokines and growth factors.…”