AM404 and VDM 11 non-specifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide.
AM404 [ N-(4-hydroxyphenyl)arachidonylamide] and VDM 11 [(5 Z,8 Z,11 Z,14 Z)- N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] are commonly used to prevent the cellular accumulation of the endocannabinoid anandamide, and thereby to potentiate its actions. However, it has been reported that AM404 can produce an influx of calcium into cells, which might be expected to have deleterious effects on cell proliferation. In the present study, AM404 and VDM 11 were found to reduce C6 glioma cell proliferation with IC(50) values of 4.9 and 2.7 microM, respectively. The inhibition of cell proliferation following a 96-h exposure was not accompanied by dramatic caspase activation, and was not prevented by either a combination of cannabinoid and vanilloid receptor antagonists, or by the antioxidant alpha-tocopherol, suggestive of a non-specific mode of action. Similar results were seen with palmitoylisopropylamide, although this compound only produced significant inhibition of cell proliferation at 30 microM concentrations. AM404 (1 microM), VDM 11 (1 microM) and palmitoylisopropylamide (3-30 microM), i.e. concentrations producing relatively modest effects on cell proliferation per se, reduced the vanilloid receptor-mediated antiproliferative effects of anandamide, as would be expected for compounds preventing the cellular accumulation of anandamide (and thereby access to its binding site on the vanilloid receptor). It is concluded that concentrations of AM404 and VDM 11 that are generally used to reduce the cellular accumulation of anandamide have deleterious effects upon cell proliferation, and that lower concentrations of these compounds may be more appropriate to use in vitro.
Jonsson
Kent-Olov
KO
Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 87, Umeå, Sweden. kentolov.jonsson@pharm.umu.se
Andersson
Anna
A
Jacobsson
Stig O P
SO
Vandevoorde
Séverine
S
Lambert
Didier M
DM
Fowler
Christopher J
CJ
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002186:Cannabinoids / Q000378:metabolism*; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D020128:Inhibitory Concentration 50; D053284:Polyunsaturated Alkamides; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism
D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; D053284:Polyunsaturated Alkamides; D011955:Receptors, Drug; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide