Deferiprone (DFP) targets cancer stem cell (CSC) propagation by inhibiting mitochondrial metabolism and inducing ROS production

Fiorillo, M, Tóth, F, Brindisi, M ORCID: https://orcid.org/0000-0002-5022-9642, Sotgia, F ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382 2020, 'Deferiprone (DFP) targets cancer stem cell (CSC) propagation by inhibiting mitochondrial metabolism and inducing ROS production' , Cells, 9 (6) , e1529.

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Abstract

Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of ~100 nM for MCF7 and an IC-50 of ~0.5 to 1 μM for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs.

Item Type: Article
Additional Information: ** From MDPI via Jisc Publications Router ** Licence for this article: https://creativecommons.org/licenses/by/4.0/ **Journal IDs: eissn 2073-4409 **History: published 23-06-2020; accepted 18-06-2020
Schools: Schools > School of Environment and Life Sciences
Journal or Publication Title: Cells
Publisher: MDPI
ISSN: 2073-4409
Related URLs:
Funders: Lunella Biotech, Inc.
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 26 Jun 2020 11:07
Last Modified: 30 Jul 2020 08:01
URI: http://usir.salford.ac.uk/id/eprint/57440

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