Cannabimimetic fatty acid derivatives in cancer and inflammation.
Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here.
Di Marzo
V
V
Istituto per la Chimica di Molecole di Interesse Biologico, Via Toiano 6, 80072, Arco Felice, Napoli, Italy. vdimarzo@icmib.na.cnr.it
Melck
D
D
De Petrocellis
L
L
Bisogno
T
T
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology; D000577:Amides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009369:Neoplasms / Q000378:metabolism*; D010169:Palmitic Acids / Q000378:metabolism* / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors
D000276:Adjuvants, Immunologic; D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D017978:Receptors, Growth Factor; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C078814:anandamide