QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.002618v1 66/6/1643    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hinz, B. Articles by Brune, K. Search for Related Content PubMed PubMed Citation Articles by Hinz, B. Articles by Brune, K.

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

Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany

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) 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 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 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 cannabinoid receptors (CB₁, CB₂) 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.

Address correspondence to: Dr. Burkhard Hinz, Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany. E-mail: hinz{at}pharmakologie.uni-erlangen.de

This article has been cited by other articles:

				P. Giussani, L. Brioschi, R. Bassi, L. Riboni, and P. Viani Phosphatidylinositol 3-Kinase/AKT Pathway Regulates the Endoplasmic Reticulum to Golgi Traffic of Ceramide in Glioma Cells: A LINK BETWEEN LIPID SIGNALING PATHWAYS INVOLVED IN THE CONTROL OF CELL SURVIVAL J. Biol. Chem., February 20, 2009; 284(8): 5088 - 5096. [Abstract] [Full Text] [PDF]

				M. D. Mitchell, T. A. Sato, A. Wang, J. A. Keelan, A. P. Ponnampalam, and M. Glass Cannabinoids stimulate prostaglandin production by human gestational tissues through a tissue- and CB1-receptor-specific mechanism Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E352 - E356. [Abstract] [Full Text] [PDF]

				R. Ramer and B. Hinz Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1 J Natl Cancer Inst, January 2, 2008; 100(1): 59 - 69. [Abstract] [Full Text] [PDF]

				H. Hasegawa, Y. Yamada, K. Komiyama, M. Hayashi, M. Ishibashi, T. Sunazuka, T. Izuhara, K. Sugahara, K. Tsuruda, M. Masuda, et al. A novel natural compound, a cycloanthranilylproline derivative (Fuligocandin B), sensitizes leukemia cells to apoptosis induced by tumor necrosis factor related apoptosis-inducing ligand (TRAIL) through 15-deoxy-{Delta}12, 14 prostaglandin J2 production Blood, September 1, 2007; 110(5): 1664 - 1674. [Abstract] [Full Text] [PDF]

				S. DeMorrow, S. Glaser, H. Francis, J. Venter, B. Vaculin, S. Vaculin, and G. Alpini Opposing Actions of Endocannabinoids on Cholangiocarcinoma Growth: RECRUITMENT OF Fas AND Fas LIGAND TO LIPID RAFTS J. Biol. Chem., April 27, 2007; 282(17): 13098 - 13113. [Abstract] [Full Text] [PDF]

				K. Gustafsson, B. Christensson, B. Sander, and J. Flygare Cannabinoid Receptor-Mediated Apoptosis Induced by R(+)-Methanandamide and Win55,212-2 Is Associated with Ceramide Accumulation and p38 Activation in Mantle Cell Lymphoma Mol. Pharmacol., November 1, 2006; 70(5): 1612 - 1620. [Abstract] [Full Text] [PDF]

				P. Pacher, S. Batkai, and G. Kunos The Endocannabinoid System as an Emerging Target of Pharmacotherapy Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462. [Abstract] [Full Text] [PDF]

				H A Patsos, D J Hicks, R R H Dobson, A Greenhough, N Woodman, J D Lane, A C Williams, and C Paraskeva The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2 Gut, December 1, 2005; 54(12): 1741 - 1750. [Abstract] [Full Text] [PDF]