Received for publication May 28, 2004.
Revised August 21, 2004.
Accepted for publication September 10, 2004.

Upregulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells

Abstract

Cannabinoids have been implicated in the reduction of glioma growth. The present study investigated a possible relationship between the recently shown induction of COX-2 expression by the endocannabinoid analogue, 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) E₂ 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 (siRNA) 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, diclofenac) and by the ceramide synthase inhibitor fumonisin B₁ which interferes with COX-2 expression by R(+)-MA. Moreover, the proapoptotic action of R(+)-MA was mimicked by the major COX-2 product PGE₂. Apoptosis and cell death by R(+)-MA were not affected by antagonists of CB₁-, CB₂- and VR₁ receptors. In further experiments, celecoxib was demonstrated to suppress apoptotic cell death elicited by anandamide which is structurally similar to R(+)-MA. Collectively, 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 co-treatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.

Key words: Cannabinoid, Prostanoid, Sphingolipids, Cyclooxygenases, Eicosanoids, Mechanisms of cell killing/apoptosis

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