Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid
Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid
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DOI：
10.1093/carcin/bgu205
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发表时间：
2014-12-01
期刊：
影响因子：
4.7
通讯作者：
Izzo, Angelo A.
中科院分区：
文献类型：
--
作者：
Borrelli, Francesca;Pagano, Ester;Izzo, Angelo A.
大麻酚(CBG)是一种安全的非精神性大麻衍生大麻素(CB)，它与致癌相关的特定靶点相互作用。具体地说，CBG能有效地阻断瞬时受体电位(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，我们调查了CBG是否可以预防结肠癌的发生。用3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑溴化法和3-氨基-7-二甲氨基-2-甲基吩嗪盐酸盐比色法检测结直肠癌细胞的生长；组织学和半胱氨酸天冬氨酸氨基转移酶3/7活性检测细胞凋亡；荧光探针检测活性氧自由基(ROS)的产生；逆转录-聚合酶链式反应(RT-PCR)定量检测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；电穿孔小发夹状RNA载体沉默TRPM8。用小鼠结肠癌模型评估CBG的体内抗肿瘤作用。结直肠癌细胞表达TRPM8、CB1、CB2、5-HT1a受体、TRPA1、TRPV1和TRPV2mRNA。CBG促进大肠癌细胞凋亡，刺激ROS生成，上调CHOP基因表达，抑制细胞生长。CBG对细胞生长的影响不依赖于TRPA1、TRPV1和TRPV2通道的激活，可被CB2受体拮抗剂进一步增强，并可被其他TRPM8通道阻断剂所模拟，但不被5-HT1A拮抗剂所模拟。此外，在TRPM8沉默的细胞中，CBG对细胞生长和CHOP mRNA表达的影响减弱。在体内，CBG抑制异种移植瘤的生长，并抑制化学诱导的结肠癌发生。CBG在体内阻止结肠癌的进展，并选择性地抑制CRC细胞的生长，这一效果与其他TRPM8拮抗剂相同。CBG在预防和治疗CRC中应被视为翻译。
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 tumour-igenesis. 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.