Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum-Targeting Copper(II) Complex |
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Authors: | Pooja Kaur Dr. Alice Johnson Joshua Northcote-Smith Dr. Chunxin Lu Dr. Kogularamanan Suntharalingam |
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Affiliation: | 1. Department of Immunology and Inflammation, Imperial College London The Hammersmith Hospital, Du Cane Road, London, W12 0NN UK;2. School of Chemistry, University of Leicester, University Road, Leicester, LE1 7RH UK;3. College of Biological, Chemical Sciences and Engineering, Jiaxing University, 56 South Yuexiu Road, Jiaxing, 314001 Zhejiang P. R. China |
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Abstract: | Immunogenic cell death (ICD) offers a method of stimulating the immune system to attack and remove cancer cells. We report a copper(II) complex containing a Schiff base ligand and a polypyridyl ligand, 4 , capable of inducing ICD in breast cancer stem cells (CSCs). Complex 4 kills both bulk breast cancer cells and breast CSCs at sub-micromolar concentrations. Notably, 4 exhibits greater potency (one order of magnitude) towards breast CSCs than salinomycin (an established breast CSC-potent agent) and cisplatin (a clinically approved anticancer drug). Epithelial spheroid studies show that 4 is able to selectively inhibit breast CSC-enriched HMLER-shEcad spheroid formation and viability over non-tumorigenic breast MCF10 A spheroids. Mechanistic studies show that 4 operates as a Type II ICD inducer. Specifically, 4 readily enters the endoplasmic reticulum (ER) of breast CSCs, elevates intracellular reactive oxygen species (ROS) levels, induces ER stress, evokes damage-associated molecular patterns (DAMPs), and promotes breast CSC phagocytosis by macrophages. As far as we are aware, 4 is the first metal complex to induce ICD in breast CSCs and promote their engulfment by immune cells. |
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Keywords: | bioinorganic chemistry cancer stem cells copper endoplasmic reticulum immunogenic cell death |
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