Salinomycin kills cancer stem cells by sequestering iron in lysosomes

Abstract

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.

Recent Progress in Ferroptosis Inducers for Cancer Therapy

“…One of the representative probe, fluorescence resonance energy transfer (FRET) Iron Probe 1 (FIP‐1) enables both detection and semiquantification of labile Fe 2+ , and was shown to identify the elevation of catalytic Fe 2+ level in MDA‐MB‐231 cells upon ferroptosis induction (Figure F) . In addition, iron in tumor tissues can be stained with Perls' Prussian Blue …”

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

“…[99,100] Salinomycin and the NBD analogue display equipotent inhibition of Wnt signaling,w hile AM5 harbored improved potencya nd selectivity towards CSCs.T he two studies both utilized their respective analogues to visualize the subcellular Figure 2. [100],c opyrightN ature Publishing Group. a) To imitate alipophilic cell membrane, two aqueous phases are separated by organic solvents, typically CHCl 3 .The central aqueousp hase is spiked with asolution of ionophore and ametal ion.…”

Strategies to diversify natural products for drug discovery

“…), an anticoccidial drug and growth promoter in animal husbandry and potent anticancer agent . A semisynthetic derivative of 65 , ironomycin ( 66 ), was found to have more potent and selective activity against breast cancer stem cells than 65 by sequestering iron from lysosomes …”