線粒體銅耗竭可抑制小鼠三陰性乳腺癌
作者：
小柯機器人發布時間：2020/10/21 17:10:19
近日，美國史丹福大學醫學院Jianghong Rao及其研究團隊發現，線粒體銅耗竭可抑制小鼠三陰性乳腺癌。該項研究成果於2020年10月19日在線發表在《自然—生物技術》雜誌上。
研究人員開發了一種安全的、靶向線粒體的、銅消耗納米顆粒（CDN），並對其進行了三陰性乳腺癌（TNBC）的測試。研究人員表明，CDN減少耗氧量和氧化磷酸化，引起代謝轉換為糖酵解，並減少TNBC細胞中的ATP產生。這種能量缺乏以及線粒體膜電位受損和氧化應激升高會導致細胞凋亡。CDN的毒性應低於現有的銅螯合劑，因為它們有利地剝奪了癌細胞線粒體中的銅，而不是全身消耗。
實際上，研究證明了CDN在健康小鼠中的低毒性。在TNBC的三種小鼠模型中，CDN的給藥可抑制腫瘤的生長並顯著提高生存率。CDN的有效性和安全性提示了這種方法的潛在臨床意義。
據介紹，線粒體銅的消耗（這將使新陳代謝從呼吸轉變為糖酵解，並降低了能量的產生）已知可以有效地抵抗依賴於氧化磷酸化的癌症類型。但是，現有的銅螯合劑對於癌症治療而言過於有毒或無效。
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