Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid

Abstract

Cannabigerol (CBG) is a safe non-psychotropic Cannabis-derived cannabinoid (CB), 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-hydroxytryptamine receptor 1A (5-HT1A) receptors and inhibits the reuptake of endocannabinoids. Here, we investigated whether CBG protects against colon tumourigenesis. Cell growth was evaluated in colorectal cancer (CRC) cells using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and 3-amino-7-dimethylamino-2-methylphenazine hydrochloride assays; apoptosis was examined by histology and by assessing caspase 3/7 activity; reactive oxygen species (ROS) production by a fluorescent probe; CB receptors, TRP and CCAAT/enhancer-binding protein homologous protein (CHOP) messenger RNA (mRNA) expression were quantified by reverse transcription-polymerase chain reaction; small hairpin RNA-vector silencing of TRPM8 was performed by electroporation. The in vivo antineoplastic effect of CBG was assessed using mouse models of colon cancer. CRC cells expressed TRPM8, CB1, CB2, 5-HT1A receptors, TRPA1, TRPV1 and TRPV2 mRNA. CBG promoted apoptosis, stimulated ROS production, upregulated CHOP mRNA and reduced cell growth in CRC 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-HT1A antagonist. 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 tumours as well as chemically induced colon carcinogenesis. CBG hampers colon cancer progression in vivo and selectively inhibits the growth of CRC cells, an effect shared by other TRPM8 antagonists. CBG should be considered translationally in CRC prevention and cure.

Genomic and Chemical Diversity inCannabis

“…However more recent quantitative trait loci (QTL) mapping experiments (Weiblen et al, 2015), expression studies (Onofri et al, 2015), and genomic analyses (van Bakel et al, 2011) paint a more complex scenario with several linked paralogs responsible for the various THCA and CBDA phenotypes. Other cannabinoids such as cannabigerol (CBG) (Borrelli et al, 2014), cannabichromene (CBC) (Izzo et al, 2012), and delta-9-tetrahydrocannabivarin (THCV) (Mcpartland et al, 2015) demonstrate pharmacological promise, and can also be produced at high levels by the plant (de Meijer and Hammond, 2005;de Meijer and Hammond, 2016;de Meijer et al, 2008). Additionally, Cannabis secondary metabolites such as terpenoids and flavonoids likely contribute to therapeutic or psychoactive effects (Russo, 2011).…”

Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration

“…The necessity for receptors to be present in order to elicit these cell killing mechanisms may not, however, be absolute; anticancer activity has been seen in leukaemia cells that is independent of the receptors (13), and similarly, minor-occurring CANNs, which have low binding affinities for these canonical receptors, are equally as active in these same cell types (14,15). Furthermore, there have been reports of CANN activity directly on cancer cells that do not usually express the receptors such as those of the breast and prostate (16).…”

Ion channels or aquaporins as novel molecular targets in gastric cancer

“…In an in vivo study, nude mice were subcutaneously injected with colon cancers cells. CBG (3 mg/kg or 10 mg/kg given intraperitoneally every day) used as treatment produced a dramatic reduction from day 3 of treatment to the end of the experiment [89]. Also, the VGSC-blocking drug phenytoin suppressed the invasion and migration of breast cancer cells in vitro.…”