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线粒体铜耗竭可抑制小鼠三阴性乳腺癌
2020-10-21 17:10
来源：小柯机器人

近日，美国斯坦福大学医学院Jianghong Rao及其研究团队发现，线粒体铜耗竭可抑制小鼠三阴性乳腺癌。该项研究成果于2020年10月19日在线发表在《自然—生物技术》杂志上。

研究人员开发了一种安全的、靶向线粒体的、铜消耗纳米颗粒（CDN），并对其进行了三阴性乳腺癌（TNBC）的测试。研究人员表明，CDN减少耗氧量和氧化磷酸化，引起代谢转换为糖酵解，并减少TNBC细胞中的ATP产生。这种能量缺乏以及线粒体膜电位受损和氧化应激升高会导致细胞凋亡。CDN的毒性应低于现有的铜螯合剂，因为它们有利地剥夺了癌细胞线粒体中的铜，而不是全身消耗。
 
实际上，研究证明了CDN在健康小鼠中的低毒性。在TNBC的三种小鼠模型中，CDN的给药可抑制肿瘤的生长并显著提高生存率。CDN的有效性和安全性提示了这种方法的潜在临床意义。
 
据介绍，线粒体铜的消耗（这将使新陈代谢从呼吸转变为糖酵解，并降低了能量的产生）已知可以有效地抵抗依赖于氧化磷酸化的癌症类型。但是，现有的铜螯合剂对于癌症治疗而言过于有毒或无效。
 
附：英文原文

Title: Mitochondrial copper depletion suppresses triple-negative breast cancer in mice

Author: Liyang Cui, Arvin M. Gouw, Edward L. LaGory, Shenghao Guo, Nabeel Attarwala, Yao Tang, Ji Qi, Yun-Sheng Chen, Zhou Gao, Kerriann M. Casey, Arkadiy A. Bazhin, Min Chen, Leeann Hu, Jinghang Xie, Mingxi Fang, Cissy Zhang, Qihua Zhu, Zhiyuan Wang, Amato J. Giaccia, Sanjiv Sam Gambhir, Weiping Zhu, Dean W. Felsher, Mark D. Pegram, Elena A. Goun, Anne Le, Jianghong Rao

Issue&Volume: 2020-10-19

Abstract: Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach. Triple-negative breast cancer is inhibited by depleting mitochondrial copper in mice.

DOI: 10.1038/s41587-020-0707-9

Source: https://www.nature.com/articles/s41587-020-0707-9

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章：《自然—生物技术》：Online/在线发表

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