Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells
Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells
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乙氧基血根碱是一种新型 AMP 激活蛋白激酶直接激活剂，可诱导自噬并在乳腺癌细胞中表现出治疗潜力
DOI：
10.3389/fphar.2019.01503
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发表时间：
2020-01
影响因子：
5.6
通讯作者：
Liu Ying
中科院分区：
文献类型：
--
作者：
Si Yuan;Wang Jiu;Liu Xuewen;Zhou Tong;Xiang Yuchen;Zhang Te;Wang Xianhui;Feng Tingting;Xu Li;Yu Qingqing;Zhao Huzi;Liu Ying
乙氧基蛇嘌呤（Eth）是一种从黄芩中提取的苯并苯胺类生物碱。它具有抗菌和抗病毒活性，为治疗呼吸综合征病毒诱导的细胞病变效应提供了治疗益处。然而，Eth对人类肿瘤的作用及其药理作用及其细胞靶点仍有待阐明。在这里，我们研究了Eth对乳腺癌（BC）细胞的影响。我们发现，在低剂量下，Eth强烈抑制BC细胞系的活力并诱导自噬。机制研究表明，Eth通过上调amp活化蛋白激酶（AMPK）的活性诱导自噬。AMPK抑制剂化合物C显著减弱eth诱导的自噬，抑制细胞增殖。同时，AMPK激活剂二甲双胍显著增强eth诱导的自噬，抑制细胞增殖。计算对接和亲和实验表明，Eth直接与AMPK的变构药物和代谢位点相互作用，稳定AMPK的活化。与正常乳腺组织相比，AMPK在肿瘤样本中的活性较低，并且与患者的预后呈负相关。此外，Eth在裸鼠中表现出强大的抗bc活性，并在大鼠中表现出良好的药代动力学。这些特性使Eth成为进一步开发和设计新的有效AMPK激活剂的有希望的候选药物。
Ethoxysanguinarine (Eth) is a benzophenanthridine alkaloid extracted from Macleaya cordata (Willd) R. Br. It possesses antibacterial and antiviral activities and offers therapeutic benefits for the treatment of respiratory syndrome virus-induced cytopathic effects. However, the effect of Eth on human tumors and its pharmacological effects remain to be elucidated, together with its cellular target. Here, we examined the effects of Eth on breast cancer (BC) cells. We found that at low doses, Eth strongly inhibited the viability of BC cell lines and induced autophagy. Mechanistic studies showed that Eth induced autophagy by upregulating the activity of the AMP-activated protein kinase (AMPK). The AMPK inhibitor compound C significantly attenuated Eth-induced autophagy and inhibited proliferation. Meanwhile, the AMPK activator metformin significantly enhanced Eth-induced autophagy and inhibited proliferation. Computational docking and affinity assays showed that Eth directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. AMPK was less activated in tumor samples compared to normal breast tissues and was inversely associated with the prognosis of the patients. Moreover, Eth exhibited potent anti-BC activity in nude mice and favorable pharmacokinetics in rats. These characteristics render Eth as a promising candidate drug for further development and for designing new effective AMPK activators.
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影响因子：
16.6
作者：
Han F;Li CF;Cai Z;Zhang X;Jin G;Zhang WN;Xu C;Wang CY;Morrow J;Zhang S;Xu D;Wang G;Lin HK
通讯作者：
Lin HK
影响因子：
--
作者：
Hardie DG;Lin SC
通讯作者：
Lin SC
影响因子：
6
作者：
Ebrahim, Nesrine;Ahmed, Inas A.;Sabry, Dina
通讯作者：
Sabry, Dina
DOI：
10.1152/ajpendo.00237.2016
发表时间：
2016-10-01
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
--
作者：
Bultot L;Jensen TE;Lai YC;Madsen AL;Collodet C;Kviklyte S;Deak M;Yavari A;Foretz M;Ghaffari S;Bellahcene M;Ashrafian H;Rider MH;Richter EA;Sakamoto K
通讯作者：
Sakamoto K
影响因子：
2.4
作者：
Y. Konda;M. Urano;Y. Harigaya;M. Onda
通讯作者：
Y. Konda;M. Urano;Y. Harigaya;M. Onda