Concomitant targeting of cyclooxygenase-2 and oxidant stress pathways for radioprotection of normal vascular tissue


Concomitant targeting of cyclooxygenase-2 and oxidant stress pathways for radioprotection of normal vascular tissue

Pietzsch, J.; Pietzsch, F.-J.; Laube, M.; Bergmann, R.; Kniess, T.; Wuest, F.

Background:

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, inflammation, and injury. This study was designed to evaluate the effects of novel selective cyclooxygenase-2 (COX-2) inhibitors on radiation-induced formation of arachidonic acid metabolites via cyclooxygenase-2 and oxidant stress pathways in endothelial cells.

Materials and methods:

Acute effects (1 d, 3 d) of X-ray radiation at moderate doses (2 to 10 Gy) without or with presence of selective COX-2 inhibitors (cyclopentene/indole/indomethacin derivatives (2 each); 1 µM, 10 µM) in human arterial (HAEC) and microvascular (HDMEC) endothelial cells compared to sham-irradiated controls were assessed. Therefore, the following parameters were measured: COX-2 induction; secretion of cytokines tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1; release of prostaglandins PGE2 and PGI2; release of isoprostanes 8-iso-PGE2 and 8-iso-PGF2α; and oxidative stress (lipid peroxides).

Results:

Irradiation of endothelial cells without presence of COX-2 inhibitors resulted in a dose-dependent augmentation of all parameters studied. When endothelial cells were exposed to COX-2 inhibitors during and for 24 h post irradiation, indole derivatives showed highest potency to inhibit release of both prostaglandins and isoprostanes. Furthermore, when irradiated cells were treated with indole derivatives a significant decrease of lipid peroxide formation and cytokine secretion could be observed, which indicates a direct interaction with oxidant stress-pathways. By contrast, both cyclopentene and indomethacin derivatives majorily inhibited prostaglandin release, but showed only slight effects on formation of isoprostanes, lipid peroxides and cytokines. Model experiments using human low density lipoproteins oxidized by radiolytically generated oxygen radicals showed that indole derivatives differently interact with peroxidation of polyunsaturated fatty acids, than the cyclopentene/indomethacin derivatives, suggesting a physico-chemical rationale for observed anti-oxidant activity.

Conclusion:

Indole-based selective COX-2 inhibitors substantially decreased radiation-induced formation of vasoactive isoprostanes
8-iso-PGE2 and 8-iso-PGF2α by endothelial cells. These findings may have particular importance in radiation-induced processes in which COX-2 is induced and oxidant stress occurs. The reduction of radiation-induced vascular dysfunction by antioxidative COX-2 inhibitors may widen the therapeutic window of cyclooxygenase-2 targeted treatment.

  • Poster
    21st Meeting of the European Association for Cancer Research (EACR-21), 26.-29.06.2010, Oslo, Norway
  • Abstract in refereed journal
    European Journal of Cancer 8(2010), 211

Permalink: https://www.hzdr.de/publications/Publ-14255
Publ.-Id: 14255