Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Death / drug effects
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Cell Death / physiology
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Cell Line
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Cell Survival / drug effects
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Cell Survival / physiology
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Click Chemistry
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Copper / metabolism*
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / physiology
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / physiology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mesenchymal Stem Cells / pathology
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Metformin / chemistry
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Metformin / pharmacology*
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondria / pathology
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Reactive Oxygen Species / metabolism
Substances
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Antineoplastic Agents
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Reactive Oxygen Species
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Copper
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Metformin
Grants and funding
Results incorporated in this article have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No [647973]), Emergence Ville de Paris, and Ligue Contre le Cancer (Equipe Labellisée). We thank the ICP-MS platform at the Institut de Physique du Globe de Paris, which is supported by IPGP multidisciplinary program PARI, and by Paris–IdF region SESAME Grant no. 12015908.