Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 1, Pages 287-291Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201710910
Keywords
antitumor agents; cancer; copper; metallopeptides; mitochondria
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Funding
- Leverhulme Early Career Fellowship [ECF-2014-178]
- KCL studentships
- Natural Science Foundation of China [21401078]
- CRUK [FC001999]
- MRC [FC001999]
- Wellcome Trust [FC001999]
- The Francis Crick Institute [10013] Funding Source: researchfish
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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.
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