【作者】 郭鹏飞； 方坚松； 陈苑； 高欣； 郭学军； 伍军军； 王奇； 张永斌；

【机构】 广州中医药大学实验动物中心； 广州中医药大学临床药理研究所；

【摘要】 癌症是造成全球大量发病率和死亡率的非常重要原因,它给世界各地的医疗系统带来了沉重的经济负担。然而,目前仍然缺乏对肿瘤患者的有效治疗。具有多药理特征的天然产物可以作为各种复杂病症(包括癌症)的新疗法。小檗碱(2,3-亚甲二氧基-9,10-二甲氧基苯酚盐酸小檗碱,BBR),是一种植物衍生化合物异喹啉季铵盐,可从多种药用植物中分离出来,如加拿大海棠(Hydrastiscanadensis),小檗属(Berberisaristata)和黄连(Coptischinensis)。多年来,之前已经提出小檗碱对许多类型的肿瘤细胞具有强大的抗癌作用,尽管确切的分子机制仍然不清楚。我们通过大量的数据挖掘(大规模文献挖掘,多数据库整合),基于系统药理学的方法[(bSDTNBI)预测,Fisher’s Test],以及网络构建和案例研究,以解释小檗碱在多种癌症治疗中的多种作用机制(MOAs)。多个数据库整合的PubMed文献挖掘收集289个靶标和29种癌症类型与小檗碱显著相关。然后筛选肿瘤靶标超过20的肿瘤类型,30种癌症类型筛选了24癌症类型相关的小檗碱,其次是靶标筛查,总结了51个靶标与小檗碱和24种癌症类型密切相关。随后,化合物-靶标(C-T),靶标-功能(T-F),化合物-靶标-疾病(C-T-D)网络构建了基于David数据库分析的富集,以阐明小檗碱在多种癌症治疗中的作用机制。Circos分析(化合物-疾病)基于Fisher’s Test检验,预测小檗碱抗癌适应症。最后,在案例研究中,我们具体阐明了小檗碱和三种密切相关的肿瘤的机制,作为验证。总之,本研究通过探索小檗碱的系统药理学,提供了一种新的方法用于开发分子靶向小檗碱的抗癌机制。更多还原

【Abstract】 Ethnopharmacologicalrelevance: Cancer, responsiblefor substantial morbidity and mortality worldwide, hasbrought a heavy economic burden to healthcare system around the world.However,currently there is still lackof effective treatment for tumor patients. Natural products with polypharmacological profiles have demonstrated promise as novel therapeutics for various complex disases,includingcancer.Berberine(2,3-methylenedioxy-9,10-dimenthoxyprotoberberine chloride,BBR), an isoquinoline quaternary alkaloid, is a plant-derived compound used in traditional Chinesemedicine that can be isolated from many kinds ofmedicinal plants such as Hydrastiscanadensis,Berberisaristata,and Coptischinensis. For many years, berberinehas been proposed to have powerful effects on many types of tumor cells although the exact molecular mechanisms are still unclear. Materials and methods: We excavated all of the targets of berberine though massive data mining(large-scaleliterature mining, multiple Databases integration), systems pharmacology-based approach [balanced substructure-drug-target network-based inference(bSDTNBI)predicted, Fisher test], network analysis and case studies to decipher the multiple mechanisms of action(MOAs) for the most widely studied berberine in various cancerstreatment. Results: The literature mining of PubMed and Databases integration resulted in 289 targets and 29 cancer types exhibiting significant correlations with berberine. Then, after screening tumor targets greater than 20, 29 cancer types were remaining for 24 cancer types related berberine, followed by target screening to sum up 51 targets closly related to both berberine and 24 cancer types. Subsequently, compound-target(C-T), target-function(T-F), compound-target-disease(C-T-D) networks and pathway enrichment based on David database analysis were constructed to illustrate the mechanisms of berberine in multiple cancer treatment. Circos plot(compound-disease) network is predicted of anticancer indications for berberine based on Fisher’s test specifically. Finally, in case studies, we elucidate the mechanism of berberine and three closely related tumors as validation under the previous study conditions. Conclusions: In summary, this study systematically provides a novel strategyfor the development of molecularly targeted the anticancer mechanisms of berberine through exploring the systems pharmacology of berberine from a holistic perspective.更多还原