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.

• MeSH
• buněčná smrt účinky léků   MeSH
• buňky PC-3 MeSH
• chelátory železa aplikace a dávkování   MeSH
• deferoxamin aplikace a dávkování   MeSH
• hem metabolismus   MeSH
• karcinogeneze účinky léků   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mitofagie účinky léků   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• pohyb buněk účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• tumor burden účinky léků   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Tamoxifen resistance remains a clinical obstacle in the treatment of hormone sensitive breast cancer. It has been reported that tamoxifen is able to target respiratory complex I within mitochondria. Therefore, we established two tamoxifen-resistant cell lines, MCF7 Tam5R and T47D Tam5R resistant to 5 μM tamoxifen and investigated whether tamoxifen-resistant cells exhibit mitochondrial changes which could help them survive the treatment. The function of mitochondria in this experimental model was evaluated in detail by studying i) the composition and activity of mitochondrial respiratory complexes; ii) respiration and glycolytic status; iii) mitochondrial distribution, dynamics and reactive oxygen species production. We show that Tam5R cells exhibit a significant decrease in mitochondrial respiration, low abundance of assembled mitochondrial respiratory supercomplexes, a more fragmented mitochondrial network connected with DRP1 Ser637 phosphorylation, higher glycolysis and sensitivity to 2-deoxyglucose. Tam5R cells also produce significantly higher levels of mitochondrial superoxide but at the same time increase their antioxidant defense (CAT, SOD2) through upregulation of SIRT3 and show phosphorylation of AMPK at Ser 485/491. Importantly, MCF7 ρ0 cells lacking functional mitochondria exhibit a markedly higher resistance to tamoxifen, supporting the role of mitochondria in tamoxifen resistance. We propose that reduced mitochondrial function and higher level of reactive oxygen species within mitochondria in concert with metabolic adaptations contribute to the phenotype of tamoxifen resistance.

• MeSH
• apoptóza MeSH
• buněčný cyklus MeSH
• chemorezistence * MeSH
• fenotyp MeSH
• glykolýza * MeSH
• hormonální protinádorové látky farmakologie   MeSH
• lidé MeSH
• mitochondrie metabolismus   patologie   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• pohyb buněk MeSH
• proliferace buněk MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• respirační komplex I metabolismus   MeSH
• superoxidy metabolismus   MeSH
• tamoxifen farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The importance of iron in the growth and progression of tumors has been widely documented. In this report, we show that tumor-initiating cells (TICs), represented by spheres derived from the MCF7 cell line, exhibit higher intracellular labile iron pool, mitochondrial iron accumulation and are more susceptible to iron chelation. TICs also show activation of the IRP/IRE system, leading to higher iron uptake and decrease in iron storage, suggesting that level of properly assembled cytosolic iron-sulfur clusters (FeS) is reduced. This finding is confirmed by lower enzymatic activity of aconitase and FeS cluster biogenesis enzymes, as well as lower levels of reduced glutathione, implying reduced FeS clusters synthesis/utilization in TICs. Importantly, we have identified specific gene signature related to iron metabolism consisting of genes regulating iron uptake, mitochondrial FeS cluster biogenesis and hypoxic response (ABCB10, ACO1, CYBRD1, EPAS1, GLRX5, HEPH, HFE, IREB2, QSOX1 and TFRC). Principal component analysis based on this signature is able to distinguish TICs from cancer cells in vitro and also Leukemia-initiating cells (LICs) from non-LICs in the mouse model of acute promyelocytic leukemia (APL). Majority of the described changes were also recapitulated in an alternative model represented by MCF7 cells resistant to tamoxifen (TAMR) that exhibit features of TICs. Our findings point to the critical importance of redox balance and iron metabolism-related genes and proteins in the context of cancer and TICs that could be potentially used for cancer diagnostics or therapy.

• MeSH
• akutní promyelocytární leukemie enzymologie   genetika   MeSH
• analýza hlavních komponent MeSH
• biologický transport MeSH
• buněčné sféroidy MeSH
• chelátory železa farmakologie   MeSH
• chemorezistence MeSH
• fenotyp MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mitochondrie enzymologie   MeSH
• myši transgenní MeSH
• nádorové kmenové buňky účinky léků   enzymologie   patologie   MeSH
• nádory prostaty farmakoterapie   enzymologie   genetika   patologie   MeSH
• nádory prsu farmakoterapie   enzymologie   genetika   patologie   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese enzymů MeSH
• regulace genové exprese u nádorů MeSH
• stanovení celkové genové exprese MeSH
• tamoxifen farmakologie   MeSH
• transkriptom * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• železo metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH