Berberine enhances the activity of Sunitinib by targeting telomere G-quadruplex  

小檗碱通过靶向端粒G-四链体增强舒尼替尼的活性（英文）

作　　者：Haitao Hou Zibing Song Jieqin Ding Dengguo Wei Sheng Hu Qianqian Zhai Xiali Yue 侯海涛;宋子冰;丁婕琴;位灯国;胡胜;翟倩倩;岳霞丽(华中农业大学理学院化学系,湖北武汉430070;湖北省肿瘤医院,湖北武汉430079)

机构地区：[1]Department of Chemistry,College of Science,Huazhong Agricultural University,Wuhan 430070,China [2]Hubei Cancer Hospital,Wuhan 430079,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2019年第5期289-297,共9页中国药学（英文版）

基　　金：Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2015RC013);The Fundamental Research Funds for the Central Universities(Grant No.2662017PY113,2662015PY208,2662015BQ048);National Natural Science Foundation of China(Grant No.21502060,21708011);Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343);Open fund of Beijing National Laboratory For Molecular Sciences

摘　　要：G-quadruplexes are stable secondary structures formed with guanine rich sequences,which are widely distributed in genome.Chemical compounds stabilizing G-quadruplexes exhibited inhibition on tumor cells.However,the feasibility of G-quadruplex structures as drug targets needs to be validated.In this study,Sunitinib,an antitumor drug targeting tyrosine kinases was found to stabilize telomere G-quadruplex.The stabilization was further enhanced by the combined usage with Berberine,an isoquinoline alkaloid.Circular dichroism spectra showed the synergistic effect comes from inducing the conformation conversion of telomere G-quadruplex.The combination of Berberine with Sunitinib resulted in 1.7-fold enhancement in cell apoptosis rate with the percentage of apoptotic cells reaching about 70%.The confocal microscopy immunofluorescence images showed the combination of Berberine and Sunitinib induced the formation of G-quadruplex at the telomere in A549 cancer cells.This study suggested that more clinic drugs could work by targeting G-quadruplex structures.鸟嘌呤富集序列可形成稳定的一种核酸二级结构, G-四链体,其广泛存在于基因组中。稳定G-四链体的化学小分子可以抑制肿瘤细胞增长,然而, G-四链体作为药物靶标的可行性还有待证实。在本研究中,我们发现靶向酪氨酸激酶治疗肿瘤的药物舒尼替尼,稳定端粒G-四链体结构。舒尼替尼与异喹啉类生物碱小檗碱的组合使用增强舒尼替尼对端粒G-四链体稳定。圆二色谱实验证明,这种的协同效应可能是由于两种药物的组合诱导了端粒末端G-四链体的构型转变。30μM小檗碱与6μM舒尼替尼联用之后,细胞凋亡率达到70%,与单独使用6μM舒尼替尼的效果相比,提高了1.7倍。荧光共聚焦显微实验表明,舒尼替尼和小檗碱联用增加人体腺癌细胞端粒末端G-四链体的形成。本研究预示很多的临床药物可能通过靶向端粒G-四链体而起作用。

关 键 词：Telomere G-quadruplex SUNITINIB BERBERINE Synergistic effects 

分 类 号：R9621[医药卫生—药理学]