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

TY - JOUR

T1 - Cyclo-oxygenase inhibitors and thromboxane synthase inhibitors differentially regulate migration arrest, growth inhibition and apoptosis in human glioma cells

AU - Kürzel, F

AU - Hagel, Christian

AU - Zapf, S

AU - Meissner, H

AU - Westphal, M

AU - Giese, A

PY - 2002/1

Y1 - 2002/1

N2 - 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 cyclo-oxygenase, 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 non-selective 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.

AB - 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 cyclo-oxygenase, 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 non-selective 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.

KW - Apoptosis/drug effects

KW - Cell Division/drug effects

KW - Cell Movement/drug effects

KW - Cyclooxygenase 1

KW - Cyclooxygenase 2

KW - Cyclooxygenase 2 Inhibitors

KW - Cyclooxygenase Inhibitors/pharmacology

KW - Enzyme Inhibitors/pharmacology

KW - Glioma/pathology

KW - Humans

KW - Isoenzymes/antagonists & inhibitors

KW - Membrane Proteins

KW - Neoplasm Invasiveness

KW - Prostaglandin-Endoperoxide Synthases

KW - Prostaglandins/biosynthesis

KW - Thromboxane-A Synthase/antagonists & inhibitors

KW - Tumor Cells, Cultured

U2 - 10.1007/s701-002-8276-9

DO - 10.1007/s701-002-8276-9

M3 - SCORING: Journal article

C2 - 11807649

VL - 144

SP - 71

EP - 87

JO - ACTA NEUROCHIR

JF - ACTA NEUROCHIR

SN - 0001-6268

IS - 1

ER -