Antiproliferative effect of deferiprone on the Hep G2 cell line

Chenoufi, Norchen; Drénou, Bernard; Loréal, Olivier; Pigeon, Christelle; Brissot, Pierre; Lescoat, Gérard

doi:10.1016/s0006-2952(98)00071-9

Cited by 34 publications

(31 citation statements)

References 26 publications

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“…This result was unanticipated, because the majority of iron chelators arrest cells at the G 1 /S boundary. 4,[28][29][30][56][57][58] Although tachpyridine preferentially binds iron, it can also bind copper and zinc, 27 and these activities may underlie its ability to arrest cells in G 2 . Alternatively or additionally, tachpyridine may induce a form of genotoxic stress different from that induced by other iron chelators, and this may trigger G 2 arrest.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike the G 2 arrest reported here for tachpyridine, cell-cycle arrest induced by other iron chelators typically occurs at the G 1 /S boundary. 4,[28][29][30][56][57][58] This effect is generally attributed to inhibition of ribonucleotide reductase, an iron-dependent enzyme 80,81 that catalyzes the rate-limiting step in DNA synthesis. For example, this enzyme is inhibited by desferrioxamine, a chelator in current clinical use in the treatment of iron overload, as well as by Triapine (Vion Pharmaceuticals, New Haven, CT), a chelator in clinical trials as an anticancer agent.…”

Section: Discussionmentioning

confidence: 99%

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Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation

Turner¹

2005

Blood

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Iron is critical for cell growth and proliferation. Iron chelators are being explored for a number of clinical applications, including the treatment of neurodegenerative disorders, heart disease, and cancer. To uncover mechanisms of action of tachpyridine, a chelator currently undergoing preclinical evaluation as an anticancer agent, cell-cycle analysis was performed. Tachpyridine arrested cells at G 2 , a radiosensitive phase of the cell cycle, and enhanced the sensitivity of cancer cells but not nontransformed cells to ionizing radiation. G 2 arrest was p53 independent and was accompanied by activation of the checkpoint kinases CHK1 and CHK2. G 2 arrest was blocked by UCN-01, a CHK1 inhibitor, but proceeded in CHK2 knock-out cells, indicating a critical role for CHK1 in G 2 arrest. Tachpyridine IntroductionIron is a metal critically important for cell proliferation and survival. It is an essential constituent of hemoglobin and myoglobin, mitochondrial electron transport proteins, hydroxylating enzymes, lipoxygenases, and cyclooxygenases, as well as ribonucleotide reductase, the enzyme that catalyzes the rate-limiting step in DNA synthesis. Tumor cells frequently exhibit increased uptake and utilization of iron, as evidenced by an increase in transferrin receptors at the cell surface. 1,2 This has led to the suggestion that agents that deplete intracellular iron may be useful in cancer therapy. [3][4][5] A variety of approaches, including the use of antisense technology 6,7 and antibodies 8 to target the transferrin receptor, have borne out this prediction. Indeed, gallium, a metal used in combination chemotherapy for the treatment of metastatic urothelial carcinoma 9 and non-Hodgkin lymphoma, 10 exerts its effects in part by interfering with iron metabolism.High-affinity, low-molecular-weight metal chelators offer a direct method of achieving intracellular iron deprivation, and the antitumor potential of iron chelators has also been the subject of active investigation. The preponderance of these studies has focused on desferrioxamine (deferoxamine, Desferal, DFO), a hexadentate iron chelator and the drug of choice for the treatment of chronic iron overload. Although desferrioxamine has been shown to retard tumor growth substantially in animal studies 11 and some clinical trials, 12 results have been mixed 13,14 and have led to the identification of chelators with potentially improved antitumor activity. For example, Triapine, a ribonucleotide reductase inhibitor and iron chelator, is currently in phase 1 clinical trials. 15 Pyridoxal isonicotinoyl hydrazone, 16 17 desferrithiocin,18,19 desferriexochelin, 20 di-2-pyridyl thiosemicarbazones, 21 and tachpyridine [22][23][24][25][26][27] are chelators under investigation as antitumor agents.Tachpyridine is a hexadentate metal chelator. 23 It is a member of a chelator family currently in preclinical development at the National Cancer Institute (NCI). Tachpyridine weakly binds divalent cations such as calcium, magnesium, and manganese, but it strongly binds iron,...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation

Turner¹

2005

Blood

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“…Iron chelators might help prevent the development of hepatocellular carcinoma and/or limit the proliferation of tumor cells (Brissot and Loreal 2002). Along this line, we previously reported the iron mobilization and the cytoprotective effect of CP20 in normal rat hepatocyte cultures (Chenoufi et al 1995), and more recently an antiproliferative effect in the human hepatoblastoma cell line HepG2 (Chenoufi et al 1998). In addition, in rat hepatoma cell line FAO and human hepatoma cell line HUH7 cultures, our results suggested that ICL670 has a higher antiproliferative effect due to its conjugated effects on both iron and polyamine metabolisms, two essential components involved in the control of cell proliferation (Lescoat et al 2007).…”

Section: Introductionmentioning

confidence: 91%

Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG

et al. 2009

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Two oral chelators, CP20 (deferiprone) and ICL670 (deferasirox), have been synthesized for the purpose of treating iron overload diseases, especially thalassemias. Given their antiproliferative effects resulting from the essential role played by iron in cell processes, such compounds might also be useful as anticancer agents. In the present study, we tested the impact of these two iron chelators on iron metabolism, in the HepaRG cell line which allowed us to study proliferating and differentiated hepatocytes. ICL670 uptake was greater than the CP20 uptake. The iron depletion induced by ICL670 in differentiated cells increased soluble transferrin receptor expression, decreased intracellular ferritin expression, inhibited (55)Fe (III) uptake, and reduced the hepatocyte concentration of the labile iron pool. In contrast, CP20 induced an unexpected slight increase in intracellular ferritin, which was amplified by iron-treated chelator exposure. CP20 also promoted Fe(III) uptake in differentiated HepaRG cells, thus leading to an increase of both the labile pool and storage forms of iron evaluated by calcein fluorescence and Perls staining, respectively. In acellular conditions, compared to CP20, iron removing ability from the calcein-Fe(III) complex was 40 times higher for ICL670. On the whole, biological responses of HepaRG cells to ICL670 treatment were characteristic of expected iron depletion. In contrast, the effects of CP20 suggest the potential involvement of this compound in the iron uptake from the external medium into the hepatocytes from the HepaRG cell line, therefore acting like a siderophore in this cell model.

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“…Cells were cultured in DMEM medium containing 10% (v/v) FBS, 2 mM Lglutamine and 1.0% penicillin-streptomycin at 37˚C in a humidified 5% CO 2 atmospheric incubator [19].…”

Section: Hepg2 Cell Culturementioning

confidence: 99%

Efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in treatment of iron-loaded hepatocyte cultures

Pangjit¹,

Banjerdpongchai²,

Phisalaphong³

et al. 2012

ABB

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Excessive iron is toxic to cells and organelles, where it can generate harmful reactive oxygen species (ROS) resulting in oxidative tissue damage. Liver is the major organ for iron storage and redox active iron in this tissue can cause fibrosis and cirrhosis in β-thalassemia patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are clinically approved iron chelators used for the treatment of patients with iron overload, but none of these chelators are completely free of side effects. In this study we report the properties of a new iron chelator 1-(Nacetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1). The labile iron pool (LIP) content was measured by using a calcein fluorescence technique and the lipidperoxidation products were quantified using the thiobarbituric acid reactive substances (TBARS) method. The cytotoxicity of CM1 was also examined with the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. CM1 was demonstrated to reduce iron-induced redox damage and to decrease the levels of the intracellular iron pool in hepatocytes. CM1 is a potentially useful iron-chelating agent which has potential to ameliorate liver iron overload and ROS-induced lipid peroxidation. CM1 is currently under investigation for oral efficacy.

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Antiproliferative effect of deferiprone on the Hep G2 cell line

Cited by 34 publications

References 26 publications

Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation

Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation

Effects of deferasirox and deferiprone on cellular iron load in the human hepatoma cell line HepaRG

Efficacy of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in treatment of iron-loaded hepatocyte cultures

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