Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid.
Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid which interacts with specific targets involved in carcinogenesis. Specifically, CBG potently blocks transient receptor potential (TRP) M8 (TRPM8), activates TRPA1, TRPV1 and TRPV2 channels, blocks 5-HT1A receptors and inhibits the reuptake of endocannabinoids. Here, we investigated whether CBG protects against colon tumorigenesis. Cell growth was evaluated in colorectal cancer cells using the MTT and NR assays; apoptosis was examined by histology and by assessing caspase 3/7 activity; ROS production by a fluorescent probe; cannabinoid (CB) receptors, TRP and CHOP mRNA expression were quantified by RT-PCR; shRNA-vector silencing of TRPM8 was performed by electroporation. The in vivo antineoplastic effect of CBG was assessed using mouse models of colon cancer. Colorectal cancer cells expressed TRPM8, CB1, CB2, 5HT1A receptors, TRPA1, TRPV1 and TRPV2 mRNA. CBG promoted apoptosis, stimulated ROS production, up-regulated CHOP mRNA and reduced cell growth in colorectal cancer cells. CBG effect on cell growth was independent from TRPA1, TRPV1 and TRPV2 channels activation, was further increased by a CB2 receptor antagonist, and mimicked by other TRPM8 channel blockers but not by a 5-HT1Aantagonist. Furthermore, the effect of CBG on cell growth and on CHOP mRNA expression was reduced in TRPM8 silenced cells. In vivo, CBG inhibited the growth of xenograft tumors as well as chemically-induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of colorectal cancer cells, an effect shared by other TRPM8 antagonists. CBG should be considered translationally in colorectal cancer prevention and cure.
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Cannabis; TRP channels; TRPM8; aberrant crypt foci; apoptosis; cannabidiol; cannabidivarin; cannabigerol; cannabinoid receptor; chemoprevention; colorectal cancer; phytocannabinoids; polyps; tumour xenograft
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