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PLoS One. 2018 Nov 6;13(11):e0206764. doi: 10.1371/journal.pone.0206764. eCollection 2018.

Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells.

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Chemical Biology of Cancer Team, Labellisée Ligue Contre le Cancer. PSL Research University, CNRS UMR3666 -INSERM U1143, Institut Curie, Paris, France.
IGF, University of Montpellier, CNRS-INSERM, Montpellier, France.
Sorbonne Universités, UPMC Université Paris 06, PSL Research University, CNRS UMR8640. Ecole Normale Supérieure, Paris, France.


The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.

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