小檗碱通过靶向端粒G-四链体增强舒尼替尼的活性

doi:10.5246/jcps.2019.05.029

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (5): 289-297.DOI: 10.5246/jcps.2019.05.029

• 【研究论文】 • 下一篇

小檗碱通过靶向端粒G-四链体增强舒尼替尼的活性

侯海涛^1#, 宋子冰^1#, 丁婕琴¹, 位灯国¹, 胡胜², 翟倩倩^1*, 岳霞丽^1*

1. 华中农业大学理学院化学系, 湖北武汉 430070
2. 湖北省肿瘤医院, 湖北武汉 430079

收稿日期:2019-03-07 修回日期:2019-03-30 出版日期:2019-05-31 发布日期:2019-04-05
通讯作者: Tel.: +86-027-87284018, E-mail: qianqianzhai@mail.hzau.edu.cn; yxl@mail.hzau.edu.cn
基金资助:
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.

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

Haitao Hou^1#, Zibing Song^1#, Jieqin Ding¹, Dengguo Wei¹, Sheng Hu², Qianqian Zhai^1*, Xiali Yue^1*

1. Department of Chemistry, College of Science, Huazhong Agricultural University, Wuhan 430070, China
2. Hubei Cancer Hospital, Wuhan 430079, China

Received:2019-03-07 Revised:2019-03-30 Online:2019-05-31 Published:2019-04-05
Contact: Tel.: +86-027-87284018, E-mail: qianqianzhai@mail.hzau.edu.cn; yxl@mail.hzau.edu.cn
Supported by:
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/Abstract

摘要：

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。30 µM小檗碱与6 µM舒尼替尼联用之后, 细胞凋亡率达到70%, 与单独使用6 µM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: 端粒G-四链体, 舒尼替尼, 小檗碱, 协同效应

Abstract:

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 percentageof 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.

Key words: Telomere G-quadruplex, Sunitinib, Berberine, Synergistic effects

中图分类号:

R962.1

Supporting:

Table S1. DNA sequences used in the FRET melting assay

Figure S1 The cytotoxic effect on A549 cancer cells of sunitinib or berberine. The cells were treated with sunitinib for 24 h or 48 h. The cells were treated with berberine for 48 h.

Table S2. The combination effects of berberine and sunitinib on A549 cancer cells.

侯海涛, 宋子冰, 丁婕琴, 位灯国, 胡胜, 翟倩倩, 岳霞丽. 小檗碱通过靶向端粒G-四链体增强舒尼替尼的活性[J]. 中国药学(英文版), 2019, 28(5): 289-297.

Haitao Hou, Zibing Song, Jieqin Ding, Dengguo Wei, Sheng Hu, Qianqian Zhai, Xiali Yue. Berberine enhances the activity of Sunitinib by targeting telomere G-quadruplex[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(5): 289-297.

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小檗碱通过靶向端粒G-四链体增强舒尼替尼的活性

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

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