Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum-Targeting Copper(II) Complex.

KAUR, Pooja, JOHNSON, Alice, NORTHCOTE-SMITH, Joshua, LU, Chunxin and SUNTHARALINGAM, Kogularamanan (2020). Immunogenic Cell Death of Breast Cancer Stem Cells Induced by an Endoplasmic Reticulum-Targeting Copper(II) Complex. ChemBioChem, 21 (24), 3618-3624.

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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.

Item Type:	Article
Uncontrolled Keywords:	bioinorganic chemistry; cancer stem cells; copper; endoplasmic reticulum; immunogenic cell death; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Survival; Coordination Complexes; Copper; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Immunogenic Cell Death; Ligands; Models, Molecular; Molecular Structure; Reactive Oxygen Species; Schiff Bases; Structure-Activity Relationship; Endoplasmic Reticulum; Humans; Breast Neoplasms; Copper; Reactive Oxygen Species; Schiff Bases; Antineoplastic Agents; Ligands; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Cell Proliferation; Cell Survival; Molecular Structure; Structure-Activity Relationship; Dose-Response Relationship, Drug; Models, Molecular; Coordination Complexes; Endoplasmic Reticulum Stress; Immunogenic Cell Death; 0304 Medicinal and Biomolecular Chemistry; 0601 Biochemistry and Cell Biology; Organic Chemistry
Identification Number:	https://doi.org/10.1002/cbic.202000553
Page Range:	3618-3624
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	11 May 2022 14:49
Last Modified:	11 May 2022 14:49
URI:	https://shura.shu.ac.uk/id/eprint/29944

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