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

Angew Chem Int Ed Engl. 2018 Jan 2;57(1):287-291. doi: 10.1002/anie.201710910. Epub 2017 Dec 5.

Abstract

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.

Keywords: antitumor agents; cancer; copper; metallopeptides; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Coordination Complexes / pharmacology*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • MAP Kinase Kinase 4 / metabolism
  • Metalloproteins / chemistry
  • Metalloproteins / pharmacology*
  • Mitochondria / drug effects*
  • Neoplastic Stem Cells / pathology*
  • Peptides / pharmacology*
  • Phenanthrolines / pharmacology*
  • Pyrans / pharmacology
  • Reactive Oxygen Species / metabolism
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Coordination Complexes
  • Metalloproteins
  • Peptides
  • Phenanthrolines
  • Pyrans
  • Reactive Oxygen Species
  • salinomycin
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • 1,10-phenanthroline