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
• 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

There is scarce evidence regarding the use of iron chelators in patients with hereditary hemochromatosis who are intolerant of phlebotomy or erythrocytapheresis. A 52-year-old man with genetically confirmed HFE hemochromatosis presented with liver disease and heart failure with severe left ventricular systolic dysfunction. Because of anemia after initial treatment, we added intravenous deferoxamine followed by oral deferiprone to less frequent erythrocytapheresis, which normalized systolic function within 1 year. Repeated cardiac magnetic resonance imaging revealed improvement of the T2* relaxation time. This report illustrates the beneficial effect of iron chelators in individuals with HFE hemochromatosis and poor tolerance of erythrocytapheresis.

• MeSH
• Iron Chelating Agents administration & dosage   MeSH
• Deferoxamine administration & dosage   MeSH
• Ventricular Dysfunction, Left diagnosis   etiology   MeSH
• Ferritins analysis   MeSH
• Hemochromatosis * blood   diagnosis   drug therapy   physiopathology   MeSH
• Cardiomyopathies * diagnosis   etiology   physiopathology   therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging, Cine methods   MeSH
• Liver Diseases diagnosis   etiology   MeSH
• Iron Overload blood   complications   MeSH
• Hemochromatosis Protein genetics   MeSH
• Pyridones administration & dosage   MeSH
• Heart Failure * diagnosis   drug therapy   etiology   MeSH
• Severity of Illness Index MeSH
• Stroke Volume MeSH
• Transferrin analysis   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• MeSH
• Deferoxamine administration & dosage   MeSH
• Humans MeSH
• Iron Overload * diagnosis   etiology   pathology   therapy   MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Porfyria cutanea tarda je i přes svůj častý výskyt v rámci diferenciální diagnózy mnohdy opomíjena. Neléčená může vést k rozvoji závažných komplikací v podobě jaterního poškození až hepatocelulárního karcinomu. Cílem článku je proto připomenout problematiku této jednotky, zejména její diagnostický algoritmus a terapii s popisem typického případu.

Porphyria cutanea tarda is often neglected in the differential diagnosis despite of its frequent occurrence. Untreated porphyria cutanea tarda can lead to serious complications in form of a hepatic lesion up to the hepatocellular carcinoma. Purpose of this article is to remind of the issue of this pathological unit, especially its diagnostic algorithm and therapy with a description of the typical case.

• MeSH
• Antimalarials therapeutic use   MeSH
• Deferoxamine administration & dosage   MeSH
• Adult MeSH
• Phlebotomy standards   MeSH
• Hydroxychloroquine administration & dosage   MeSH
• Skin Manifestations MeSH
• Humans MeSH
• Liver Diseases diagnosis   etiology   metabolism   MeSH
• Porphyrins urine   MeSH
• Porphyria Cutanea Tarda * drug therapy   classification   blood   urine   MeSH
• Sunscreening Agents therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

Železo (Fe) je základní složkou hemoglobinu a myoglobinu, a má proto nezastupitelnou funkci v přenosu kyslíku. Je také kofaktorem důležitých enzymů: kataláz, ribonukleotidreduktáz, peroxidáz, cytochromoxidáz, akonitáz. Tyto enzymy katalyzují řadu chemických reakcí důležitých pro přežití organismu, jako je mitochondriální respirace či syntéza nukleových kyselin (DNA i RNA) a důležitých proteinů, a účastní se buněčné proliferace, diferenciace a apoptózy.1 Je tedy prvkem zcela nezbytným pro život. Jak nedostatek Fe, tak i jeho nadbytek je pro organismus škodlivý. Při nedostatku železa dochází k rozvoji sideropenické anemie, která je poměrně snadno léčitelná. Nadbytečná akumulace železa představuje ve svých důsledcích mnohem závažnější ohrožení než jeho nedostatek.

• MeSH
• Iron Chelating Agents administration & dosage   MeSH
• Deferoxamine administration & dosage   adverse effects   MeSH
• Benzoic Acid adverse effects   therapeutic use   MeSH
• Humans MeSH
• Iron Overload diagnosis   drug therapy   prevention & control   MeSH
• Pyridones administration & dosage   adverse effects   MeSH
• Triazoles adverse effects   therapeutic use   MeSH
• Check Tag
• Humans MeSH

Iron (Fe) chelators are used clinically for the treatment of Fe overload disease. Iron also plays a role in the pathology of many other conditions, and these potentially include the cardiotoxicity induced by catecholamines such as isoprenaline (ISO). The current study examined the potential of Fe chelators to prevent ISO cardiotoxicity. This was done as like other catecholamines, ISO contains the classical catechol moiety that binds Fe and may form redox-active and cytotoxic Fe complexes. Studies in vitro used the cardiomyocyte cell line, H9c2, which was treated with ISO in the presence or absence of the chelator, desferrioxamine (DFO), or the lipophilic ligand, 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH). Both of these chelators were not cardiotoxic and significantly reduced ISO cardiotoxicity in vitro. However, PCTH was far more effective than DFO, with the latter showing activity only at a high, clinically unachievable concentration. Further studies in vitro showed that interaction of ISO with Fe(II)/(III) did not increase cytotoxic radical generation, suggesting that this mechanism was not involved. Studies in vivo were initiated using rats pretreated intravenously with DFO or PCTH before subcutaneous administration of ISO (100 mg/kg). DFO at a clinically used dose (50 mg/kg) failed to reduce catecholamine cardiotoxicity, while PCTH at an equimolar dose totally prevented catecholamine-induced mortality and reduced cardiotoxicity. This study demonstrates that PCTH reduced ISO-induced cardiotoxicity in vitro and in vivo, demonstrating that Fe plays a role, in part, in the pathology observed.

• MeSH
• Cell Line MeSH
• Iron Chelating Agents pharmacology   MeSH
• Deferoxamine administration & dosage   MeSH
• Financing, Organized MeSH
• Isoproterenol antagonists & inhibitors   metabolism   toxicity   MeSH
• Myocytes, Cardiac metabolism   drug effects   MeSH
• Catecholamines antagonists & inhibitors   metabolism   toxicity   MeSH
• Rats MeSH
• Oxidation-Reduction MeSH
• Rats, Wistar MeSH
• Thiophenes pharmacology   MeSH
• Iron metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH

Nadbytek železa v organizmu může vznikat v důsledku jeho nadměrného přívodu, při poruše transportu železa či při poruše jeho utilizace. V našich podmínkách jde nejčastěji o dědičnou hemochromatózu či anémie s vysokým stupněm inefektivní erytropoézy s nutností podávání opakovaných transfuzí erytrocytů (např. myelodysplastický syndrom). Klíčovým momentem v patofyziologii toxicity nadbytku železa je jeho zvýšený výdej do cirkulace. Při překročení saturace transferinu železem stoupá v plazmě množství tzv. netransferinového železa, jehož součást, tzv. labilní plazmatické železo, je oxidačně aktivní a může iniciovat peroxidaci lipidů vedoucí k zániku buněk. V laboratorní diagnostice nadbytku železa se uplatňuje vyšetření feritinu v séru a saturace transferinu, mezi neinvazivní metody sloužící ke kvantifikaci obsahu železa v tkáních patří NMR jater a srdce. V léčbě dědičné hemochromatózy se uplatňuje kombinace erytrocytoferéz a chelatační léčby. Ta je metodou volby u anémií s přetížením železem. V současné době jsou k dispozici 3 chelatační přípravky: desferioxamine, deferiprone a deferasirox a cílem jejich podávání není jen odstranění již vzniklého přetížení železem, ale prevence jeho vzniku a toxického působení volného železa.

• Keywords
• nadbytek železa v organizmu, dědičná hemochromatóza, saturace transferinu, labilní plazmatické železo, feritin v séru, chelatační léčba,
• MeSH
• Iron Chelating Agents therapeutic use   MeSH
• Cytapheresis methods   utilization   MeSH
• Deferoxamine administration & dosage   adverse effects   therapeutic use   MeSH
• Ferritins isolation & purification   blood   MeSH
• Hemochromatosis diagnosis   genetics   therapy   MeSH
• Hemosiderosis diagnosis   genetics   therapy   MeSH
• Clinical Laboratory Techniques utilization   MeSH
• Humans MeSH
• Mass Screening methods   utilization   MeSH
• Iron Metabolism Disorders diagnosis   etiology   therapy   MeSH
• Iron Overload diagnosis   etiology   therapy   MeSH
• Anemia, Sideroblastic diagnosis   genetics   therapy   MeSH
• Transferrin isolation & purification   MeSH
• Check Tag
• Humans MeSH

• Keywords
• L1-deferiprone,
• MeSH
• Iron Chelating Agents administration & dosage   pharmacology   therapeutic use   MeSH
• Chelation Therapy methods   MeSH
• Deferoxamine administration & dosage   pharmacology   therapeutic use   MeSH
• Adult MeSH
• Ferritins blood   MeSH
• Cardiomyopathies diagnosis   drug therapy   MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Thalassemia drug therapy   MeSH
• Treatment Outcome MeSH
• Iron metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Comparative Study MeSH

• Keywords
• Deferiprone (L1), ICL670 (deferasirox), GT56-252, L1NAll,
• MeSH
• Iron Chelating Agents administration & dosage   pharmacology   therapeutic use   MeSH
• Chelation Therapy economics   methods   MeSH
• Deferoxamine administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Thalassemia drug therapy   MeSH
• Iron MeSH
• Check Tag
• Humans MeSH

• MeSH
• beta-Thalassemia drug therapy   MeSH
• Chelation Therapy * MeSH
• Deferiprone administration & dosage   MeSH
• Deferoxamine administration & dosage   MeSH
• Child MeSH
• Adult MeSH
• Liver MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Magnetic Resonance Imaging instrumentation   MeSH
• Adolescent MeSH
• Liver Diseases prevention & control   MeSH
• Heart Diseases prevention & control   MeSH
• Iron Overload * MeSH
• Heart MeSH
• Statistics as Topic MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Randomized Controlled Trial MeSH