Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity

doi:10.1186/s12885-019-5914-8

	Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity
	Wang,Ning1,2,3 ; Fan,Yanhua 1,2; Yuan,Chun-Mao 1,2; Song,Jialei 1,2; Yao,Yao 1,2; Liu,Wuling 1,2; Gajendran,Babu 1,2; Zacksenhaus,Eldad 3,4; Li,Yanmei 1,2; Liu,Jielin 5; Hao,Xiao Jiang 1,2; Ben-David,Yaacov 1,2
通讯作者	Liu,Jielin(liujlin63@yahoo.com) ; Hao,Xiao Jiang(haoxj@mail.kib.ac.cn) ; Ben-David,Yaacov(yaacovbendavid@hotmail.com)
	2019-08-02
发表期刊	BMC Cancer
ISSN	1471-2407
卷号	19 期号:1
摘要	AbstractBackgroundMAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available.MethodA library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541–43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia.ResultsCompounds A1541–43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541–43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541–43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541–43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541–43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia.ConclusionsThis study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.
关键词	Cancer Leukemia Chinese medicinal plant Melia azedarach Drug screen ERK1/2 agonists Differentiation Apoptosis
DOI	10.1186/s12885-019-5914-8
语种	英语
WOS记录号	BMC:10.1186/s12885-019-5914-8
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/67741
专题	植物化学与西部植物资源持续利用国家重点实验室
通讯作者	Liu,Jielin; Hao,Xiao Jiang; Ben-David,Yaacov
作者单位	1. 2. 3. 4. 5.
推荐引用方式 GB/T 7714	Wang,Ning,Fan,Yanhua,Yuan,Chun-Mao,et al. Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity[J]. BMC Cancer,2019,19(1).
APA	Wang,Ning.,Fan,Yanhua.,Yuan,Chun-Mao.,Song,Jialei.,Yao,Yao.,...&Ben-David,Yaacov.(2019).Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity.BMC Cancer,19(1).
MLA	Wang,Ning,et al."Selective ERK1/2 agonists isolated from Melia azedarach with potent anti-leukemic activity".BMC Cancer 19.1(2019).