Premium
A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells
Author(s) -
Laws Kristine,
BinevaTodd Ganka,
Eskandari Arvin,
Lu Chunxin,
O'Reilly Nicola,
Suntharalingam Kogularamanan
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201710910
Subject(s) - mitochondrion , breast cancer , cancer research , stem cell , cancer stem cell , apoptosis , microbiology and biotechnology , biology , in vitro , chemistry , cancer , biochemistry , genetics
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.