A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

作者：Kristine Laws, Ganka Bineva‐Todd, Arvin Eskandari, Chunxin Lü, Nicola O’Reilly, Kogularamanan Suntharalingam · 发表于：Angewandte Chemie International Edition · 年份：2017 · DOI：10.1002/anie.201710910 · 被引用次数：116 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、Histone Deacetylase Inhibitors Research

The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10-phenanthroline)copper(II) and various organelle-targeting peptide sequences is reported. The mitochondria-targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non-CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC-potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.