一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长

doi:10.5246/jcps.2018.09.061

中国药学(英文版) ›› 2018, Vol. 27 ›› Issue (9): 600-607.DOI: 10.5246/jcps.2018.09.061

一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长

雷丽, 陈宇, 杨思敏, 孟祥豹, 余四旺^*

北京大学医学部药学院化学生物学系, 北京 100191

收稿日期:2018-06-05 修回日期:2018-07-11 出版日期:2018-09-29 发布日期:2018-08-12
通讯作者: Tel.: +86-010-82805140, E-mail: swang_yu@hsc.pku.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81472657 and 81273370).

A novel aza-naphthoquinone inhibits tumor growth by inducing apoptosis

Li Lei, Yu Chen, Simin Yang, Xiangbao Meng, Siwang Yu^*

State Key Laboratory of Natural and Biomimetic Drugs; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2018-06-05 Revised:2018-07-11 Online:2018-09-29 Published:2018-08-12
Contact: Tel.: +86-010-82805140, E-mail: swang_yu@hsc.pku.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81472657 and 81273370).

摘要/Abstract

摘要：

自发现天然产物甲萘醌具有通过抑制IDO-1酶介导的抗肿瘤活性以来, 萘醌类化合物如吡喃萘醌引起了广泛的科研关注。在本研究中, 我们基于6,7-二氯喹啉-5,8-二酮合成了一类新型的氮杂萘醌类化合物并进行了细胞毒筛选, 发现其中CY-26-11的活性最佳。Annexin-V染色结果显示, CY-26-11浓度依赖地诱导A549人肺腺癌细胞凋亡。进一步的数据显示CY-26-11可下调抗凋亡蛋白Bcl-2, 上调促凋亡蛋白Bax以及Puma, 并激活caspase-3。最后, CY-26-11在小鼠路易斯肺癌皮下移植瘤模型中取得良好的抑瘤效果。总之, 我们的实验结果说明CY-26-11具有良好的不依赖于IDO-1活性的体内外抗肿瘤作用, 并为萘醌类化合物提供了抗肿瘤新机制。

关键词: 萘醌, CY-26-11, 细胞凋亡, 抗肿瘤活性

Abstract:

Natural product menaquinone has been reported to exhibit antitumor activity mediated by inhibiting IDO-1 enzyme, and naphthoquinone compounds like pyranaphthoquinone have attracted extensive research interests since they share the naphthoquinone pharmacophores. In the present study, a novel series of aza-naphthoquinones was synthesized based on 6,7-dichloroquinoline-5,8-dione structure, and their cytotoxicities were screened using lung cancer cells. Among them CY-26-11was identified as the most potent one. CY-26-11 concentration-dependently induced apoptosis in A549 human lung adenocarcinomacells, as indicated by annexin-V staining. Further experimental data show that CY-26-11 down-regulated Bcl-2 while up-regulatedBax and Puma protein levels, and activated caspase-3. Finally, CY-26-11 significantly inhibited the growth of Lewis lung carcinomaxenografts in vivo without significant major toxicities. Taken together, our results demonstrate that CY-26-11 exhibited IDO-1-independent anti-tumor effects both in vitro and in vivo, providing a new anti-tumor mechanism for naphthoquinonecompounds.

Key words: Naphthoquinone, CY-26-11, Apoptosis, Anti-tumor activity

中图分类号:

R915

Supporting:

雷丽, 陈宇, 杨思敏, 孟祥豹, 余四旺. 一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长[J]. 中国药学(英文版), 2018, 27(9): 600-607.

Li Lei, Yu Chen, Simin Yang, Xiangbao Meng, Siwang Yu. A novel aza-naphthoquinone inhibits tumor growth by inducing apoptosis[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(9): 600-607.

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一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长

A novel aza-naphthoquinone inhibits tumor growth by inducing apoptosis

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