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.
Carcinogenesis. 2014 Dec;35(12):2787-97. doi: 10.1093/carcin/bgu205. Epub 2014 Sep 30.
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.
大麻二醇（CBG）是一种安全的非精神活性大麻衍生大麻素（CB），可与参与致癌作用的特定靶标相互作用。具体而言，CBG 可有效阻断瞬时受体电位（TRP）M8（TRPM8），激活 TRPA1、TRPV1 和 TRPV2 通道，阻断 5-羟色胺受体 1A（5-HT1A）受体并抑制内源性大麻素的再摄取。在这里，我们研究了 CBG 是否可以预防结肠癌。使用 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴盐和 3-氨基-7-二甲基氨基-2-甲基吩嗪盐酸盐测定法评估结直肠癌细胞（CRC）中的细胞生长；通过组织学检查和评估半胱天冬酶 3/7 活性来检查细胞凋亡；通过荧光探针检测活性氧（ROS）的产生；通过逆转录-聚合酶链反应定量 CB 受体、TRP 和 CCAAT/增强子结合蛋白同源蛋白（CHOP）信使 RNA（mRNA）的表达；通过电穿孔进行小发夹 RNA 载体沉默 TRPM8。使用结肠癌小鼠模型评估 CBG 的体内抗肿瘤作用。CRC 细胞表达 TRPM8、CB1、CB2、5-HT1A 受体、TRPA1、TRPV1 和 TRPV2 mRNA。CBG 促进 CRC 细胞凋亡，刺激 ROS 产生，上调 CHOP mRNA 并降低细胞生长。CBG 对细胞生长的作用独立于 TRPA1、TRPV1 和 TRPV2 通道的激活，被 CB2 受体拮抗剂进一步增强，并被其他 TRPM8 通道阻滞剂模拟，但不被 5-HT1A 拮抗剂模拟。此外，沉默 TRPM8 会降低 CBG 对细胞生长和 CHOP mRNA 表达的影响。在体内，CBG 抑制异种移植物肿瘤的生长以及化学诱导的结肠癌发生。CBG 阻碍结直肠癌的体内进展，并选择性地抑制 CRC 细胞的生长，这是其他 TRPM8 拮抗剂的共同作用。CBG 应该在 CRC 的预防和治疗中得到考虑。
