Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells

We have previously identified thromboxane synthase as an important regulator of glioma cell migration. Inhibitors of this enzyme abrogate cell motility and induce apoptosis. However, the formation rate of thromboxanes is indirectly dependent on the activity of cyclooxygenase, which represents the rate-limiting step in the synthesis of prostaglandins and thromboxanes. In this study we have analyzed the expression of COX-1 and COX-2 in glioma cell lines and biopsies of glial tumors. In normal glia no expression of both COX isoforms was present, however, reactive astrocytes and glial tumors of all grades demonstrated expression of both COX-1 and COX-2. In contrast to inhibitors of thromboxane synthase, selective and nonselective cyclo-oxygenase inhibitors did not block cell motility. Specific COX 2 inhibitors resulted in growth inhibition and induction of intracellular DNA fragmentation indicative of apoptotic cell death. Treatment of glioma cells with thromboxane synthase inhibitors had a synergistic effect on induction of apoptosis by camptothecin, whereas COX inhibitors had not. Furthermore, combined treatment using COX-2 inhibitors and specific thromboxane synthase inhibitors did not show a synergistic increase of apoptosis. These data indicate that COX inhibitors and thromboxane synthase inhibitors influence apoptosis in glioma cells through different pathways. We hypothesize that, in contrast to the COX-2 inhibitors, thromboxane synthase inhibitors block the invasive phenotype of glioma cells and therefore increase the pro-apoptotic disposition of the cells and increase the susceptibility to induced apoptosis. This effect may be independent of prostaglandin synthesis controlled by cyclo-oxygenases.