Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice.
OBJECTIVES
Whether and how synthetic cannabinoids affect inflammation and carcinogenesis has not been well studied. The present study was thus conducted to assess effects of synthetic cannabinoids on inflammation and carcinogenesis in vivo in mice.


METHODS
Twenty-three analogues of synthetic cannabinoids were isolated from, and identified as adulterants in, illegal drugs distributed in the Tokyo metropolitan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, selected cannabinoids, JWH-018, -122 and -210, were studied for their effects on carcinogenesis induced in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA.


KEY FINDINGS
Among cannabinoids, naphthoylindoles mostly exhibited superior inhibitory effects against TPA-induced ear oedema and, especially, JWH-018, -122 and -210 showed potent activity with 50% inhibitory dose (ID50) values of 168, 346 and 542 nm, respectively (an activity corresponding to that of indometacin (ID50 = 908 nm)). Furthermore these three compounds also markedly suppressed the tumour-promoting activity of TPA.


CONCLUSIONS
This is the first report indicating the structure-activity relationships for the anti-inflammatory activity of synthetic cannabinoids on TPA-induced inflammation in mice. Naphthoylindoles, JWH-018, -122 and -210, had the most potent anti-inflammatory activity and also markedly inhibited tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. The present results suggest that synthetic cannabinoids, such as JWH-018, -122 and -210, may be used as cancer chemopreventive agents in the future.
["Nakajima|Jun'ichi|J|", 'Nakae|Dai|D|', 'Yasukawa|Ken|K|']
D015127:9,10-Dimethyl-1,2-benzanthracene D000818:Animals D000893:Anti-Inflammatory Agents D000970:Antineoplastic Agents D002186:Cannabinoids D003043:Cocarcinogenesis D003877:Dermatitis, Contact D005260:Female D051379:Mice D008813:Mice, Inbred ICR D015394:Molecular Structure D012878:Skin Neoplasms D013329:Structure-Activity Relationship D013755:Tetradecanoylphorbol Acetate
synthetic cannabinoids 12-O-tetradecanoylphorbol-13-acetate anti-inflammatory effect anti-tumour-promoting agent two-stage carcinogenesis