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Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic
Francesca Borrelli1, Ester Pagano1, Barbara Romano1
1Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy, Department of Diagnostic Services (Anatomy and Pathologic Histology Service), Ospedale dei Pellegrini, ASL 1, 80135 Naples, Italy, Institute of Biomolecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy and Institute of Protein Biochemistry, National Research Council, Via P. Castellino 111, 80131 Naples, Italy.
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.
Insights
Cannabigerol (CBG), a non-psychotropic cannabinoid, shows promise in colon cancer prevention and treatment. CBG inhibits colorectal cancer cell growth and progression by targeting TRPM8 channels, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Pharmacology
- Cannabinoid Research
Background:
- Cannabigerol (CBG) is a non-psychotropic cannabinoid derived from Cannabis.
- CBG interacts with various molecular targets, including transient receptor potential (TRP) channels and serotonin receptors, implicated in carcinogenesis.
- The role of CBG in colon cancer (CRC) development and progression is not fully understood.
Purpose of the Study:
- To investigate the protective effects of CBG against colon tumourigenesis.
- To elucidate the mechanisms underlying CBG's action in colorectal cancer cells.
- To evaluate the in vivo antineoplastic efficacy of CBG in colon cancer models.
Main Methods:
- In vitro assessment of cell growth, apoptosis, and reactive oxygen species (ROS) production in CRC cells.
- Quantification of gene expression for cannabinoid receptors, TRP channels, and CHOP mRNA.
- In vivo studies using mouse models of colon cancer, including xenografts and chemically induced carcinogenesis.
Main Results:
- CBG demonstrated potent inhibition of colorectal cancer cell growth and promoted apoptosis.
- CBG-induced effects were linked to TRPM8 channel activity and CHOP upregulation, independent of other TRP channels.
- In vivo, CBG significantly inhibited tumor growth in both xenograft and chemically induced colon cancer models.
Conclusions:
- Cannabigerol (CBG) exhibits significant anti-tumorigenic effects in colon cancer.
- CBG's mechanism involves TRPM8 channel antagonism, leading to reduced cell proliferation and enhanced apoptosis.
- CBG warrants further investigation as a potential therapeutic agent for colorectal cancer prevention and treatment.
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