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

Fiorillo, M; Tóth, F; Brindisi, M; Sotgia, F; Lisanti, MP

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


Authors

M Fiorillo

F Tóth

M Brindisi

F Sotgia

MP Lisanti



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.

Citation

Fiorillo, M., Tóth, F., Brindisi, M., Sotgia, F., & Lisanti, M. (2020). Deferiprone (DFP) targets cancer stem cell (CSC) propagation by inhibiting mitochondrial metabolism and inducing ROS production. Cells, 9(6), e1529. https://doi.org/10.3390/cells9061529

Journal Article Type Article
Acceptance Date Jun 18, 2020
Publication Date Jun 23, 2020
Deposit Date Jun 26, 2020
Publicly Available Date Jun 26, 2020
Journal Cells
Publisher MDPI
Volume 9
Issue 6
Pages e1529
DOI https://doi.org/10.3390/cells9061529
Keywords iron chelators, CSCs, ROS, deferiprone, mitochondrial metabolism, FDA-approved drugs
Publisher URL https://doi.org/10.3390/cells9061529
Related Public URLs http://www.mdpi.com/journal/cells
Additional Information 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