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Salinomycin kills cancer stem cells by sequestering iron in lysosomes
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Journal Article
Salinomycin kills cancer stem cells by sequestering iron in lysosomes
2017
Overview
Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs
in vitro
and
in vivo
, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.
Cancer stem cells are typically refractory to conventional treatments. Now, an unprecedented mechanism has been discovered by which salinomycin and derivatives can sequester iron in lysosomes leading to cytoplasmic iron depletion and the subsequent production of reactive oxygen species that are lethal to the cell. This discovery of the importance of iron in cancer stem cell maintenance provides an opportunity for developing new therapeutics.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ Breast Neoplasms - pathology
/ Cancer
/ Cell Proliferation - drug effects
/ Cell Survival - drug effects
/ Drug Screening Assays, Antitumor
/ Female
/ Ferritin
/ Humans
/ Iron
/ Neoplastic Stem Cells - drug effects
/ Neoplastic Stem Cells - metabolism
/ Neoplastic Stem Cells - pathology
/ Reactive Oxygen Species - analysis
/ Reactive Oxygen Species - metabolism
/ Tumors
