The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Kalinowski, Danuta S.; Richardson, Des R.

doi:10.1124/pr.57.4.2

Cited by 643 publications

(795 citation statements)

References 233 publications

(409 reference statements)

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“…Chelators are widely investigated because of their therapeutic potential in the treatment of metal overload and diseases related to imbalanced metal homeostasis including hemochromatosis, β-thalassemia, Alzheimer's or Parkinson's diseases and cancer [8,9,12,70].…”

Section: Discussionmentioning

confidence: 99%

“…According to this model, increased glycolysis compensates for the higher energy demand created by the "futile cycling" of the transporter [79,81,82], but the oxidative stress associated with oxidative phosphorylation ultimately results in the selective apoptosis of MDR cells [83]. ROS have not only been implicated in the paradoxical sensitivity of resistant cells, but also in the mechanism of toxicity of chelators [8,12,13].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

See 1 more Smart Citation

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Pape

Tóth

Füredi

et al. 2016

European Journal of Medicinal Chemistry

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“…D epriving cancer cells of the essential nutrient iron (Fe) is a novel approach for cancer treatment (1)(2)(3). Fe-containing proteins perform key reactions involved in energy metabolism and DNA synthesis.…”

mentioning

confidence: 99%

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

Whitnall

Howard²,

Ponka³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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453

644

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Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established therapies. Iron (Fe) is critical for cell-cycle progression and DNA synthesis and potentially represents a novel molecular target for the design of new anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe chelators using human tumors. In this investigation, the ligands showed broad antitumor activity and could overcome resistance to established antitumor agents. The in vivo efficacy of the most effective chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT-and vehicletreated mice, probably because of the very low doses required to induce anticancer activity. Dp44mT caused up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 in the tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action.cancer ͉ di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone ͉ Ndrg1

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“…L1 may also prevent URO accumulation by the formation of an Fe-L1 chelate that is not redox-active. 19,28 Other iron chelates such as Fe-ethylene diamine tetraacetic acid 29 and Fe-nitrilotriacetate 30 stimulate CYP1A2-catalyzed microsomal oxidation of uroporphyrinogen to URO (Fig. 1), a reaction that is considered to play a critical role in the development of uroporphyria in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we evaluated the effectiveness of iron deficiency caused by the removal of hepatic iron with the oral iron chelator deferiprone (L1), a clinically used iron chelator. 19 The complete prevention of uroporphyria was achieved by an intermediate dose of L1, which only partially depleted hepatic iron.…”

mentioning

confidence: 99%

Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda

Gorman¹,

Zaharia²,

Trask³

et al. 2007

Hepatology

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Porphyria cutanea tarda is a liver disease characterized by elevated hepatic iron and excessive production of uroporphyrin (URO). Phlebotomy is an effective treatment that probably acts by reducing hepatic iron. Here we used Hfe(؊/؊) mice to compare the effects on hepatic URO accumulation of two different methods of hepatic iron depletion: iron chelation using deferiprone (L1) versus iron-deficient diets. Hfe(؊/؊) mice in a 129S6/SvEvTac background were fed 5-aminolevulinic acid (ALA), which results in hepatic URO accumulation, and increasing doses of L1 in the drinking water. Hepatic URO accumulation was completely prevented at low L1 doses, which partially depleted hepatic nonheme iron. By histological assessment, the decrease in hepatic URO accumulation was associated with greater depletion of iron from hepatocytes than from Kupffer cells. The L1 treatment had no effect on levels of hepatic cytochrome P4501A2 (CYP1A2). L1 also effectively decreased hepatic URO accumulation in C57BL/6 Hfe(؊/؊) mice treated with ALA and a CYP1A2 inducer. ALA-treated mice maintained on defined iron-deficient diets, rather than chow diets, did not develop uroporphyria, even when the animals were iron-supplemented either directly in the diet or by iron dextran injection. Conclusion: The results suggest that dietary factors other than iron are involved in the development of uroporphyria and that a modest depletion of hepatocyte iron by L1 is sufficient to prevent URO accumulation. (HEPATOLOGY

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The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Cited by 643 publications

References 233 publications

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics

Effect of an oral iron chelator or iron-deficient diets on uroporphyria in a murine model of porphyria cutanea tarda

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