glyceryl-2-arachidonate and Central-Nervous-System-Neoplasms

Nuclear factor (NF)-κB is the key transcription factor involved in the inflammatory responses, and its activation aggravates tumors. Peptidoglycan (PGN), a main cell wall component of Gram-positive bacteria, stimulates Toll-like receptor 2 (TLR-2) and activates a number of inflammatory pathways, including NF-κB. Cannabinoids have been reported to exert anti-inflammatory and antitumor effects. The mechanisms underlying these actions, however, are largely unknown. The purpose of this study was to investigate whether cannabinoids can suppress the PGN-induced activation of NF-κB and cell growth via cannabinoid receptors in U87MG human malignant glioma cells. PGN treatment induced the phosphorylation of NF-κB and cell proliferation in a concentration-dependent manner. The main endocannabinoid, 2-arachidonoylglycerol, prevented the PGN-induced phosphorylation of NF-κB, which was reversed by the CB1 cannabinoid receptor antagonist, AM281. The synthetic cannabinoid, WIN55,212-2, abolished the PGN-activated cell growth, and this effect was reversed by AM281. The preferential expression of CB1 rather than CB2 receptors in these cells was confirmed by reverse transcription-mediated polymerase chain reaction experiments and the observation that the WIN55,212-2-induced morphological changes were completely reversed by AM281 but not by the CB2 antagonist, AM630. Our finding that cannabinoids suppress the NF-κB inflammatory pathway and cell growth via CB1 receptors in glioma cells provides evidence for the therapeutic potential of targeting cannabinoid receptors for the treatment of inflammation-dependent tumor progression.

Topics: Antineoplastic Agents; Arachidonic Acids; Benzoxazines; Cannabinoids; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endocannabinoids; Glioma; Glycerides; Humans; Morpholines; Naphthalenes; NF-kappa B; Peptidoglycan; Phosphorylation; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2