最佳大麻素-萜烯组合比例抑制正常和化生食管细胞中胃反流的致突变性。

文献信息

中文摘要

背景： 食管腺癌（EAC）常源于长期暴露于酸和胆汁反流，其中次级胆汁酸如脱氧胆酸（DCA）通过涉及活性氧（ROS）、氧化性DNA损伤和凋亡抵抗的机制参与其发病。人体内源性大麻素系统（ECS）调节多种抗炎、抗氧化和镇痛通路，这些通路与疾病调节有关，并可能抵消胃食管反流的有害影响。尽管具有治疗前景，但有效激活ECS的药理学方法仍具挑战性。
目的： 评估针对ECS的特定大麻素-萜烯组合是否能减轻食管细胞模型中胆汁酸诱导应激的致突变和细胞毒性效应，并评估ECS相关蛋白受体在EAC进展中的临床意义。
方法： 将暴露于DCA的人食管上皮细胞，以及经受低pH和胆汁酸混合物的Barrett食管细胞系，用不同比例植物大麻素和萜烯处理。终点包括DNA损伤、线粒体膜电位和ROS产生，以确定最佳化合物组合。通过免疫组织化学评估临床样本中ECS相关受体蛋白的表达。
结果： 大麻萜酚与植醇的1:5比例显著减少了DCA诱导的DNA损伤，保持了线粒体膜电位，并降低了ROS水平。该组合还促进了受损细胞的凋亡并降低了致突变性。患者样本分析表明，ECS相关受体蛋白CB1的表达与EAC进展相关，表明ECS调节在癌症预防中具有更广泛的临床作用。
结论： 使用系统选择的大麻素-萜烯比例调节ECS可以减轻胆汁酸诱导的食管损伤，并可能减少癌变进展。这些发现支持进一步的体内研究，并提出了将大麻素-萜烯治疗扩展到其他具有类似致病机制的疾病的可能性。

英文摘要

BACKGROUND: Esophageal adenocarcinoma (EAC) frequently arises from chronic exposure to acid and bile reflux, with secondary bile acids, such as deoxycholic acid (DCA), contributing to its pathogenesis through mechanisms involving reactive oxygen species (ROS), oxidative DNA damage, and resistance to apoptosis. The human endocannabinoid system (ECS) regulates diverse anti-inflammatory, antioxidant, and analgesic pathways implicated in disease modulation and may counteract the harmful effects of gastroesophageal reflux. Despite its therapeutic promise, effective pharmacological activation of the ECS remains challenging.
AIM: To evaluate whether specific cannabinoid-terpene combinations targeting the ECS could attenuate the mutagenic and cytotoxic effects of bile acid-induced stress in esophageal cell models, and to assess the clinical significance of ECS-related protein receptors in the progression of EAC.
METHODS: Human esophageal epithelial cells exposed to DCA, as well as a Barrett's esophagus cell line subjected to low potential of hydrogen and a bile acid cocktail, were treated with various ratios of phyto-cannabinoids and terpenes. Endpoints included DNA damage, mitochondrial membrane potential, and ROS production to identify optimal compound combinations. Expression of ECS-related receptor proteins in clinical samples was assessed by immunohistochemistry.
RESULTS: A 1:5 ratio of cannabigerol to phytol significantly reduced DCA-induced DNA damage, preserved mitochondrial membrane potential, and decreased ROS levels. This combination also promoted apoptosis in damaged cells and reduced mutagenicity. Analysis of patient samples demonstrated that expression of the ECS-associated receptor protein CB1 correlated with EAC progression, indicating a broader clinical role for ECS modulation in cancer prevention.
CONCLUSION: Modulation of the ECS using systematically selected cannabinoid-terpene ratios can attenuate bile acid-induced esophageal damage and may reduce carcinogenic progression. These findings support further in vivo studies and raise the possibility of expanding cannabinoid-terpene therapeutics to other diseases with comparable pathogenic mechanisms.