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Vol. 299, Issue 3, 951-959, December 2001

Inhibition of Rat C6 Glioma Cell Proliferation by Endogenous and Synthetic Cannabinoids. Relative Involvement of Cannabinoid and Vanilloid Receptors

Stig O. P. Jacobsson , Thomas Wallin and Christopher J. Fowler

Departments of Pharmacology and Clinical Neuroscience (S.O.P.J., T.W., C.J.F.) and Odontology (S.O.P.J.), Umeå University, Umeå, Sweden

The effects of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) upon rat C6 glioma cell proliferation were examined and compared with a series of synthetic cannabinoids and related compounds. Cells were treated with the compounds each day and cell proliferation was monitored for up to 5 days of exposure. AEA time- and concentration-dependently inhibited C6 cell proliferation. After 4 days of treatment, AEA and 2-AG inhibited C6 cell proliferation with similar potencies (IC50 values of 1.6 and 1.8 µM, respectively), whereas palmitoylethanolamide showed no significant antiproliferative effects at concentrations up to 10 µM. The antiproliferative effects of both AEA and 2-AG were blocked completely by a combination of antagonists at cannabinoid receptors (SR141716A and SR144528 or AM251 and AM630) and vanilloid receptors (capsazepine) as well as by alpha -tocopherol (0.1 and 10 µM), and reduced by calpeptin (10 µM) and fumonisin B1 (10 µM), but not by L-cycloserine (1 and 100 µM). CP 55,940, JW015, olvanil, and arachidonoyl-serotonin were all found to affect C6 glioma cell proliferation (IC50 values of 5.6, 3.2, 5.5, and 1.6 µM, respectively), but the inhibition could not be blocked by cannabinoid + vanilloid receptor antagonists. It is concluded that the antiproliferative effects of the endocannabinoids upon C6 cells are brought about by a mechanism involving combined activation of both vanilloid receptors and to a lesser extent cannabinoid receptors, and leading to oxidative stress and calpain activation. However, there is at present no obvious universal mechanism whereby plant-derived, synthetic, and endogenous cannabinoids affect cell viability and proliferation.

0022-3565/01/2993-0951$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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