Details

Autor(en) / Beteiligte

• Hinz, Burkhard
• Ramer, Robert
• Eichele, Karin
• Weinzierl, Ulrike
• Brune, Kay

Titel

Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma Cells

Ist Teil von

• Molecular pharmacology, 2004-12, Vol.66 (6), p.1643-1651

Ort / Verlag

United States: American Society for Pharmacology and Experimental Therapeutics

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• Cannabinoids have been implicated in the reduction of glioma growth. The present study investigated a possible relationship between the recently shown induction of cyclooxygenase (COX)-2 expression by the endocannabinoid analog R (+)methanandamide [R(+)-MA] and its effect on the viability of H4 human neuroglioma cells. Incubation with R(+)-MA for up to 72 h decreased the cellular viability and enhanced accumulation of cytoplasmic DNA fragments in a time-dependent manner. Suppression of R(+)-MA-induced prostaglandin (PG) E 2 synthesis with the selective COX-2 inhibitor celecoxib (0.01-1 μM) or inhibition of COX-2 expression by COX-2-silencing small-interfering RNA was accompanied by inhibition of R(+)-MA-mediated DNA fragmentation and cell death. In contrast, the selective COX-1 inhibitor SC-560 was inactive in this respect. Cells were also protected from apoptotic cell death by other COX-2 inhibitors (NS-398 {[ N -[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide]} and diclofenac) and by the ceramide synthase inhibitor fumonisin B 1 , which interferes with COX-2 expression by R(+)-MA. Moreover, the proapoptotic action of R(+)-MA was mimicked by the major COX-2 product PGE 2 . Apoptosis and cell death by R(+)-MA were not affected by antagonists of cannabinoid receptors (CB 1 , CB 2 ) and vanilloid receptor 1. In further experiments, celecoxib was demonstrated to suppress apoptotic cell death elicited by anandamide, which is structurally similar to R(+)-MA. As a whole, this study defines COX-2 as a hitherto unknown target by which a cannabinoid induces apoptotic death of glioma cells. Furthermore, our data show that pharmacological concentrations of celecoxib may interfere with the proapoptotic action of R(+)-MA and anandamide, suggesting that cotreatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.