Mitochondrial copper depletion suppresses triple-negative breast cancer in mice

• Published in: Nature biotechnology Vol. 39; no. 3; pp. 357 - 367
• Main Authors: Cui, Liyang, Gouw, Arvin M., LaGory, Edward L., Guo, Shenghao, Attarwala, Nabeel, Tang, Yao, Qi, Ji, Chen, Yun-Sheng, Gao, Zhou, Casey, Kerriann M., Bazhin, Arkadiy A., Chen, Min, Hu, Leeann, Xie, Jinghang, Fang, Mingxi, Zhang, Cissy, Zhu, Qihua, Wang, Zhiyuan, Giaccia, Amato J., Gambhir, Sanjiv Sam, Zhu, Weiping, Felsher, Dean W., Pegram, Mark D., Goun, Elena A., Le, Anne, Rao, Jianghong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2021; Nature Publishing Group
• Subjects: 631/67/2321; 631/67/2327; 639/925/352/152; 639/925/352/2734; Adenosine triphosphate; Agriculture; Animal models; Animals; Apoptosis; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Breast cancer; Care and treatment; Cell Death; Cell Line, Tumor; Chelating agents; Chelating Agents - metabolism; Composition; Copper; Copper - metabolism; Depletion; Disease Models, Animal; Electron transport; Female; Glycolysis; Humans; Life Sciences; Membrane potential; Mice; Mitochondria; Mitochondria - metabolism; Nanoparticles; Oxidative Phosphorylation; Oxidative stress; Oxygen consumption; Phosphorylation; Physiological aspects; Toxicity; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; United States
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-020-0707-9

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.