Targeting cyclooxygenase-2 and oxidant stress pathways for attenuation of radiation-induced vascular dysfunction

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 investigation was performed in order to evaluate the effects of novel selective cyclooxygenase-2 (Cox-2) inhibitors (coxibs) on radiation-induced formation of eicosanoids via Cox-2 and oxidant stress pathways in both human arterial endothelial cells (EC model) and rat aortic rings (AR model), respectively. In order to assess acute effects (24 h) of X-ray radiation at moderate doses (2, 4, and 10 Gy) without or with presence of coxibs (EC model: cyclopentene/indole/indomethacin derivatives; AR model: indole derivatives; celecoxib as reference) compared to sham-irradiated controls, the following parameters were measured: Cox-2 protein induction, release of prostaglandins, release of isoprostanes, and formation of lipid and protein oxidation products (LO/PO). Irradiation of EC and AR without presence of coxibs resulted in a dose-dependent augmentation of all parameters studied. When EC and AR were exposed to Cox-2 inhibitors (0.1, 1, and 10 µM), during and for 24 h post irradiation, indole derivatives showed highest potency to inhibit release of both prostaglandins and isoprostanes. Furthermore, indole derivatives significantly decreased LO/PO formation, indicating a direct interaction with oxidant stress-pathways. By contrast, both cyclopentene and indomethacin derivatives (and celecoxib) mainly inhibited prostaglandin release, but showed only slight effects on formation of isoprostanes and LO/PO. Model experiments using human low density lipoproteins showed that indole derivatives differently interact with oxidation of polyunsaturated fatty acids and protein amino acid side chains, than the cyclopentene/indomethacin derivatives, suggesting a physico-chemical rationale for observed antioxidative activity. The reduction of radiation-induced vascular dysfunction by antioxidative coxibs may widen the therapeutic window of Cox-2 targeted treatment.