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Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid.
Carcinogenesis 2014; 35(12):2787-97C

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.

Authors+Show Affiliations

Department 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.Department 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.Department 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.Department 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.Department of Diagnostic Services (Anatomy and Pathologic Histology Service), Ospedale dei Pellegrini, ASL 1, 80135 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 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.Department 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 aaizzo@unina.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25269802

Citation

Borrelli, Francesca, et al. "Colon Carcinogenesis Is Inhibited By the TRPM8 Antagonist Cannabigerol, a Cannabis-derived Non-psychotropic Cannabinoid." Carcinogenesis, vol. 35, no. 12, 2014, pp. 2787-97.
Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014;35(12):2787-97.
Borrelli, F., Pagano, E., Romano, B., Panzera, S., Maiello, F., Coppola, D., ... Izzo, A. A. (2014). Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis, 35(12), pp. 2787-97. doi:10.1093/carcin/bgu205.
Borrelli F, et al. Colon Carcinogenesis Is Inhibited By the TRPM8 Antagonist Cannabigerol, a Cannabis-derived Non-psychotropic Cannabinoid. Carcinogenesis. 2014;35(12):2787-97. PubMed PMID: 25269802.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. AU - Borrelli,Francesca, AU - Pagano,Ester, AU - Romano,Barbara, AU - Panzera,Stefania, AU - Maiello,Francesco, AU - Coppola,Diana, AU - De Petrocellis,Luciano, AU - Buono,Lorena, AU - Orlando,Pierangelo, AU - Izzo,Angelo A, Y1 - 2014/09/30/ PY - 2014/10/2/entrez PY - 2014/10/2/pubmed PY - 2015/2/15/medline SP - 2787 EP - 97 JF - Carcinogenesis JO - Carcinogenesis VL - 35 IS - 12 N2 - 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. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/25269802/Colon_carcinogenesis_is_inhibited_by_the_TRPM8_antagonist_cannabigerol_a_Cannabis_derived_non_psychotropic_cannabinoid_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgu205 DB - PRIME DP - Unbound Medicine ER -