文献类型：期刊文献

英文题名：Mitochondrial copper depletion suppresses triple-negative breast cancer in mice

作者：Cui, Liyang[1];Gouw, Arvin M.[2,3];LaGory, Edward L.[4];Guo, Shenghao[5,6,7];Attarwala, Nabeel[5,6,7];Tang, Yao[8];Qi, Ji[9];Chen, Yun-Sheng[1,10];Gao, Zhou[11];Casey, Kerriann M.[12];Bazhin, Arkadiy A.[13];Chen, Min[1];Hu, Leeann[14];Xie, Jinghang[1];Fang, Mingxi[1];Zhang, Cissy[5,6,7];Zhu, Qihua[1,15];Wang, Zhiyuan[9];Giaccia, Amato J.[4];Gambhir, Sanjiv Sam[1];Zhu, Weiping[8];Felsher, Dean W.[2,3];Pegram, Mark D.[16];Goun, Elena A.[13];Le, Anne[5,6,7];Rao, Jianghong[1]

机构：[1]Stanford Univ, Dept Radiol, Sch Med, Mol Imaging Program Stanford, Stanford, CA 94305 USA;[2]Stanford Univ, Dept Med, Sch Med, Div Oncol, Stanford, CA 94305 USA;[3]Stanford Univ, Dept Pathol, Sch Med, Div Oncol, Stanford, CA 94305 USA;[4]Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA;[5]Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA;[6]Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA;[7]Johns Hopkins Univ, Sch Med, ChemBE, Baltimore, MD USA;[8]East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[9]Chinese Acad Sci, Changchun Inst Appl Chem, State Key Lab Polymer Phys & Chem, Changchun, Peoples R China;[10]Univ Illinois, Dept Elect & Comp Engn, Urbana, IL USA;[11]Stanford Univ, Genet Bioinformat Serv Ctr, Stanford, CA 94305 USA;[12]Stanford Univ, Dept Comparat Med, Sch Med, Stanford, CA 94305 USA;[13]Swiss Fed Inst Technol Lausanne EPFL, Sch Basic Sci, Inst Chem Sci & Engn, Lausanne, Switzerland;[14]Salk Inst Biol Studies, San Diego, CA USA;[15]China Pharmaceut Univ, Dept Med Chem, Nanjing, Peoples R China;[16]Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

年份：2021

卷号：39

期号：3

起止页码：357

外文期刊名：NATURE BIOTECHNOLOGY

收录：;EI(收录号：20204309374031);WOS:【SCI-EXPANDED(收录号:WOS:000579694700003)】；

基金：L.C. acknowledges support from the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award W81XWH-18-1-0591. A.M.G. and M.C. acknowledge support by the Stanford Cancer Translational Nanotechnology Training T32 training grant funded by the National Cancer Institute (grant T32 CA196585). This work was also supported by the US National Institutes of Health (NIH) National Cancer Institute grant R01CA243033 (to J.R.), grant R01CA184384 (to D.W.F.), grant R01CA208735 (to D.W.F.), grant R01CA193895 (A.L.), grant R35CA197713 (to A.J.G.) and the Shared Instrument Grant (1S10OD025226-01 to A.L.) funded by the NIH. We acknowledge the use of the Mass Spectrometry Facility, the Department of Chemistry NMR Facility, the SCi3 Core Facility, the Neuroscience Microscopy Service Facility (NIH grant NS069375), the Cell Sciences Imaging Facility, the Animal Histology Services and Diagnostic Lab at the Veterinary Service Center and the Genetics Bioinformatics Service Center at Stanford University. We thank A. Olson for his expertise with tissue preparation and imaging by confocal microscopy, and J. Rosenburg and T. Liang for their assistance in biostatistical analysis.

语种：英文

外文关键词：Mammals - Mitochondria - Phosphorylation - Cancer cells - Diseases - Pathology - Metabolism - Cell death - Chelation

摘要：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.