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Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy
C. Sandoval-Acuña, N. Torrealba, V. Tomkova, SB. Jadhav, K. Blazkova, L. Merta, S. Lettlova, MK. Adamcová, D. Rosel, J. Brábek, J. Neuzil, J. Stursa, L. Werner, J. Truksa
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1941 to 1 year ago
Freely Accessible Science Journals
from 1941 to 1 year ago
Open Access Digital Library
from 1941-01-01
Open Access Digital Library
from 1941-01-01
- MeSH
- Cell Death drug effects MeSH
- PC-3 Cells MeSH
- Iron Chelating Agents administration & dosage MeSH
- Deferoxamine administration & dosage MeSH
- Heme metabolism MeSH
- Carcinogenesis drug effects MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Mitochondria drug effects metabolism MeSH
- Mitophagy drug effects MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- Neoplasms drug therapy metabolism pathology MeSH
- Cell Movement drug effects MeSH
- Cell Proliferation drug effects MeSH
- Reactive Oxygen Species metabolism MeSH
- Signal Transduction drug effects MeSH
- Tumor Burden drug effects MeSH
- Xenograft Model Antitumor Assays MeSH
- Iron metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.
Faculty of Sciences BIOCEV Research Center Charles University Vestec Czech Republic
Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic
School of Medical Science Griffith University Southport Queensland Australia
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