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(ϩ)-methanandamide [R(ϩ)-MA] and its effect on the viability of H4 human neuroglioma cells. Incubation with R(ϩ)-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(ϩ)-MA-induced prostaglandin (PG) E 2 synthesis with the selective COX-2 inhibitor celecoxib (0.01-1 M) or inhibition of COX-2 expression by COX-2-silencing small-interfering RNA was accompanied by inhibition of R(ϩ)-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(ϩ)-MA. Moreover, the proapoptotic action of R(ϩ)-MA was mimicked by the major COX-2 product PGE 2 . Apoptosis and cell death by R(ϩ)-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(ϩ)-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(ϩ)-MA and anandamide, suggesting that cotreatment with COX-2 inhibitors could diminish glioma regression induced by these compounds.

This study demonstrates COX-2 induction and synthesis of L-PGDS-derived, PPARgamma-activating PGs as a possible mechanism of apoptosis by MA.

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Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the antiinvasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time-and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.

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