[Hereditary iron overload]. / Surcharges héréditaires en fer.

The field of hereditary iron overload has known, in the recent period, deep changes mainly related to major advances in molecular biology. It encompasses now a series of genetic entities. The mechanistic understanding of iron overload development and iron toxicity has greatly improved. The diagnostic approach has become essentially noninvasive with a major role for biological tests. From the therapeutic viewpoint, the phlebotomy treatment is now enriched by the possibility of resorting to oral chelation and by innovative perspectives directly linked to our improvement in the molecular understanding of these diseases.

[Haemochromatoses. New understanding, new treatments]. / Les hémochromatoses. Nouvelle compréhension, nouveaux traitements.

Haemochromatoses encompass a variety of genetic iron overload diseases. The most frequent entity remains HFE-related haemochromatosis. The other syndromes include diseases related to mutations of the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Iron excess is due to deficiencies in either hepcidin or ferroportin, the two key regulatory proteins of iron metabolism. Diagnosis rests essentially upon non invasive clinical, biological and imaging criteria. The mainstay of iron overload treatment is venesection therapy in case of hepcidin deficiency, the therapeutic approach for the future being hepcidin supplementation. In ferroportin deficiency, oral chelation is an interesting orientation. The recent creation in France of a reference center and of several competence centers for rare genetic iron overload diseases represents a valuable organization for improving both the understanding of the diseases and the management of the patients.

[Gaucher's disease in Rennes University hospital: a 10-year retrospective study]. / Etude rétrospective sur dix ans des patients atteints de maladie de Gaucher au CHU de Rennes.

INTRODUCTION: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease. METHODS: We performed a 10-year retrospective study of patients with GD followed-up in the Rennes University teaching hospital. RESULTS: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status. CONCLUSION: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD.

Antiproliferative and apoptotic effects in rat and human hepatoma cell cultures of the orally active iron chelator ICL670 compared to CP20: a possible relationship with polyamine metabolism.

OBJECTIVE: Iron loading has been observed to have a hyperproliferative effect on hepatocytes in vitro and on tumour cells in vivo; removal of this iron being required to induce antitumour activity. MATERIAL AND METHODS: Antiproliferative effects of orally active tridentate iron chelator ICL670 (deferasirox) and bidentate iron chelator CP20 (deferiprone), mediated through the chelation of intracellular iron, were compared in rat hepatoma cell line FAO and human hepatoma cell line HUH7. RESULTS: In FAO cell cultures, we have shown that ICL670 decreased cell viability and DNA replication and induced apoptosis more efficiently than an iron-binding equivalent concentration of CP20. Moreover, ICL670 decreased significantly the number of the cells in G(2)-M phase. In the HUH7 cell cultures, ICL670 and a four-time higher iron-binding equivalent concentration of CP20, decreased cell viability and DNA replication in the same range. CP20 increased the number of the cells in G(2)-M phase. However, ICL670 inhibited polyamine biosynthesis by decreasing ornithine decarboxylase mRNA level; in contrast, CP20 increased polyamine biosynthesis, particularly putrescine level, by stimulating spermidine-spermine N(1)-acetyl transferase activity that could activate the polyamine retro-conversion pathway. By mass spectrometry, we observed that ICL670 cellular uptake was six times higher than CP20. CONCLUSIONS: These results suggest that ICL670 has a powerful antitumoural effect and blocks cell proliferation in neoplastic cells by a pathway different from that of CP20 and may constitute a potential adjuvant drug for anticancer therapy.

Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states.

In hemochromatosis and other disorders associated with iron overload, a significant fraction of the total iron in plasma circulates in the form of low molecular weight complexes not bound to transferrin. Efficient and unregulated clearance of this form of iron by the liver may account for the hepatic iron loading and toxicity that characterize these diseases. We tested this possibility by examining the hepatic removal process for representative iron complexes in the single-pass perfused rat liver. Hepatic uptake of both ferrous and ferric 55Fe from ultrafiltered human serum was found to be highly efficient and effectively irreversible (single-pass extraction of 1 microM iron, 58-75%). Similar high efficiencies were seen for iron complexed to specific physiologic and nonphysiologic coordinators, including histidine, citrate, fructose, oxalate and glutamate, and tricine. Because of lower plasma flow rates, single-pass extraction of these iron complexes in vivo should be even greater. Autoradiography confirmed that most iron had been removed by parenchymal cells. Hepatic removal from Krebs-tricine buffer was saturable with similar kinetic parameters for ferrous and ferric iron (apparent Km, 14-22 microM; V max, 24-38 nmol min-1 g liver-1). These findings suggest that high levels of non-transferrin-bound iron in plasma may be an important cause of hepatic iron loading in iron overload states.

Effects of phlebotomy therapy on cytochrome P450 2e1 activity and oxidative stress markers in dysmetabolic iron overload syndrome: a randomized trial.

AIM: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. METHODS: Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. RESULTS: In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). CONCLUSIONS: In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.

Stearoyl coenzyme A desaturase 1 expression and activity are increased in the liver during iron overload.

In humans, hepatic iron overload can lead to hepatocellular carcinoma development. Iron related dysregulation of hepatic genes could play a role in this phenomenon. We previously found that the carbonyl-iron overloaded mouse was a useful model to study the mechanisms involved in the development of hepatic lesions related to iron excess. The aim of the present study was to identify hepatic genes overexpressed in conditions of iron overload by using this model. A suppressive subtractive hybridization was performed between hepatic mRNAs extracted from control and 3% carbonyl-iron overloaded mice during 8 months. This methodology allowed us to identify stearoyl coenzyme A desaturase 1 (SCD1) mRNA overexpression in the liver of iron loaded mice. The corresponding enzymatic activity was also found to be significantly increased. In addition, we demonstrated that both SCD1 mRNA expression and activity were increased in another iron overload model in mice obtained by a single iron-dextran subcutaneous injection. Moreover, we found, in both models, that SCD1 mRNA was not only influenced by the quantity of iron in the liver but also by the duration of iron overload since SCD1 mRNA upregulation was not detected in earlier stages of iron overload. In addition, we found that cellular repartition likely influenced SCD1 mRNA expression. In conclusion, we demonstrated that iron excess in the liver induced both the expression of SCD1 mRNA and its corresponding enzymatic activity. The level and duration of iron overload, as well as cellular repartition of iron excess in the liver likely play a role in this induction. The fact that the expression and activity of SCD1, an enzyme adding a double bound into saturated fatty acids, are induced in two models of iron overload in mice leads to the conclusion that iron excess in the liver may enhance the biosynthesis of unsaturated fatty acids.

[HFE hemochromatosis: pathogenic and diagnostic approach]. / Hémochromatose HFE: approche pathogénique et diagnostique.

HFE hemochromatosis is the most frequent genetic iron overload disease. It is linked to the C282Y mutation of the HFE protein, protein encoded by the HFE gene, which is located on chromosome 6. The mechanisms accounting for iron excess are not only digestive hyperabsorption of iron but also excessive recycling of macrophagic iron coming from erythrophagocytosis and secreted into the blood. Both mechanisms are linked to an HFE-related hepatic failure in producing hepcidin, a key hormone of body iron regulation. The marked phenotypic variability of C282Y homozygosity expression is likely related to both genetic and environmental factors. The HFE gene discovery has rendered non invasive the positive diagnostic of HFE hemochromatosis, which is now based first on an increased level of plasma transferrin saturation leading to the request of the HFE mutation. Then, hepatic MRI is a reliable method to quantify iron overload. The HFE gene discovery has also paved the road of an enlarged field of differential diagnoses corresponding to novel entities of non-HFE related genetic iron overload syndromes.

Chronic iron overload inhibits protein secretion by adult rat hepatocytes maintained in long-term primary culture.

Short-term pure cultures and long-term cocultures of adult rat hepatocytes with rat liver epithelial cells, presumably derived from primitive biliary cells, were used to define in vitro models of iron overloaded hepatocytes in order to understand the molecular mechanism responsible for liver damage occurring in patients with hemochromatosis. In vitro iron overload was obtained by daily addition of ferric nitrilotriacetate to the culture medium. A concentration of 20 microM ferric salt induced hepatocyte iron overload with minimal cytotoxicity as evaluated by cell viability, morphological changes of treated cells and cytosolic enzyme leakage into the culture medium. The effects of iron overload on protein biosynthesis and secretion were studied in both short-term pure cultures and long-term cocultures of hepatocytes. The amounts of intracellular and newly synthesized proteins were never modified by the iron treatment. Furthermore, neither the relative amounts of transferrin and albumin mRNAs nor their translational products were altered by iron overload. Moreover, no change in the transferrin isomeric forms were observed in treated cells. In contrast, a prolonged exposure of cocultured hepatocytes to 20 microM ferric salt led to a significant decrease in the amount of proteins secreted in the medium. This decrease included the two major secreted proteins, namely albumin and transferrin, and probably all other secreted proteins. These results demonstrate that iron loading alters neither the total nor the liver specific protein synthesis activity of cultured hepatocytes. They suggest that chronic overload may impede the protein secretion process.

EPR study of antioxidant activity of the iron chelators pyoverdin and hydroxypyrid-4-one in iron-loaded hepatocyte culture: comparison with that of desferrioxamine.

Iron supplementation of hepatocyte culture induced the production of lipid-derived radicals as shown by spin-trapping with alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (POBN). The EPR signal corresponding to POBN/lipid-derived radicals (aN = 15.6 G aH = 2.6 G) was concentration dependent on iron (Fe-NTA) added to the culture medium (50, 100, 200 microM). It was also incubation time dependent (0 to 24 h). The EPR signal could be used as a marker for iron-induced lipid peroxidation. The antioxidant activity of two iron chelators, pyoverdin (Pa) and hydroxypyrid-4-one derivative (CP20) was compared with that of desferrioxamine (DFO) on iron-loaded hepatocyte culture. These compounds (100 microM) were tested either in pretreatment or simultaneously with Fe-NTA (100 microM). In each procedure, the EPR signal obtained from the cells supplemented with iron was substantially reduced in the presence of either DFO or CP20 but not with Pa. Moreover, the DFO and CP20 but not Pa showed protective effect on the leakage of the intracellular enzyme lactate dehydrogenase into the culture medium. The present study described a specific spin-trapping technique in conjunction with EPR spectroscopy that is able to demonstrate the cytoprotective effect of iron chelators, as shown by the elimination of lipid-derived radicals in iron-loaded hepatocyte culture.

Transient transcriptional inhibition of the transferrin gene by cyclic AMP.

Transferrin mRNA content and gene transcription rate were measured in the liver of rats submitted to iron overload or depletion, castration, treatment with sexual steroid hormones, glucagon and cyclic AMP. The influence of puberty in males and females and of pregnancy was also analysed. Glucagon and cyclic AMP reduced mRNA level by about 50% at the 12th hour of treatment and transferrin gene transcription by as much as 95% at the 30th minute of drug infusion, with a secondary increase of the transcription rate for a protracted treatment. None of the other hormones tested had any detectable effect on transferrin gene expression, the same being true for iron overload or depletion.

Antioxidant and free radical scavenging activities of the iron chelators pyoverdin and hydroxypyrid-4-ones in iron-loaded hepatocyte cultures: comparison of their mechanism of protection with that of desferrioxamine.

The protective effect on iron-supplemented hepatocyte cultures of three iron chelators, pyoverdin Pa and hydroxypyrid-4-one derivatives CP20 and CP22, was compared to that of the widely known desferrioxamine B (Desferal:DFO), on the basis of two criteria: (a) their effectiveness in inhibiting free malondialdehyde (MDA) production as an index of iron-induced lipid peroxidation; and (b) their ability to reduce intracellular enzyme leakage. In view of these two markers of iron toxicity, the protective effect of these chelators was classified as follows: DFO > CP20 > or = CP22 > Pa. The mechanism of cellular protection was elucidated by investigating both the iron-chelating activity and the free radical scavenging property of these agents. As concerns the iron chelation, DFO and Pa exerted the same rank order as for cytoprotection (DFO > Pa). The free radical scavenging property toward hydroxyl radical .OH and peroxyl radical ROO. was investigated in a cell-free experimental model. The two siderophores, DFO and Pa, appeared to have a lower antiradical activity toward .OH than hydroxypyrid-4-one CP22. This .OH scavenging activity was classified as follows: CP22 >> Pa > DFO. Moreover, the chelators exhibited for the quenching of ROO. the same order of effectiveness as that observed for cellular protection: DFO > CP20 > or = CP22 > Pa. These data indicate that, in addition to the iron-chelating activity which represents the most important property for determining the protection capacity of these iron chelators, their free radical scavenging ability also must be taken into account. This direct demonstration of a strong association between the free radical scavenging activity and the protective effect of iron chelators further increases the prospects for the development and clinical applications of new oral chelating drugs.

Lysosomal enzyme activities during ageing of adult human liver cell lines.

Ten lysosomal enzyme activities have been compared during the growth and ageing of adult human liver cell lines. Arylsulfatase A, beta-D-galactosidase and beta-D-glucuronidase activities were significantly lower and arylsulfatase B activity was significantly higher in senescent cells than in actively growing cells. Furthermore, hexosaminidase activity was lower and acid phosphatase activity higher in old cells in every cell line tested but the differences were not significant. On the other hand, no change occurred in alpha-L-fucosidase, alpha-D-mannosidase, alpha-D-galactosidase and alpha-D-glucosidase activities. These results demonstrate that the increase in size and number of secondary lysosomes during ageing is accompanied for a few lysosomal enzymes by an increase or a decrease in activity depending on the enzyme.

Mössbauer spectroscopy study of iron overloaded livers.

Absorption 57Fe Mössbauer spectra have been carried out directly on fresh or lyophylized tissues of liver with either normal iron depot or iron overload. Two types of overloading have been studied: primary iron overload due to an excessive intestinal iron absorption and secondary iron overload (hemosiderosis) produced in beta-thalassemia patients by hypertransfusional therapeutics. The Mössbauer spectra, at room temperature, 77 and 4.2 K, on normal liver samples, are typical for the ferritin-hemosiderin compounds. In the spectra, performed on hemosiderosis liver samples, there appears, in addition to ferritin and hemosiderin, a new iron molecular environment, typical of high spin ferric iron and characterized by a superparamagnetic behaviour which begins at high temperature (above 77 K). This new component does not show up in the primary iron overload cases and seems characteristic of the physiological process which induces the iron overload.

A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis.

The aim of this study was to describe the histologic pattern of iron distribution in end-stage cirrhosis due to various causes and to test the reliability of the hepatic iron index (equal to hepatic iron concentration divided by age) in excluding or confirming associated hemochromatosis in such a condition. Large slices of the resected livers of 30 patients transplanted for alcoholic and/or viral end-stage cirrhosis were assessed histologically for iron distribution and biochemically for hepatic iron concentration in the least and the most iron-overloaded nodules of each case. HLA-A3 was used as the marker for the hemochromatosis gene in the population studied. Intranodular parenchymal siderosis was found in 23 cases (12 spotty, 11 diffuse) with diffuse intrabiliary iron deposits apparent in only two cases. Although in 14 patients the hepatic iron index was significantly high (> 1.9) so as to suggest hemochromatosis, these cases did not correspond to homozygous hemochromatosis with respect to the prevalence of HLA-A3 antigen. End-stage cirrhosis arising from different causes is frequently complicated by parenchymal siderosis that may mimic hemochromatosis, including a hepatic iron index greater than 1.9. The diagnosis of hemochromatosis in patients with end-stage cirrhosis, even those with a hepatic iron index greater than 1.9, should rely mainly on clinical and histologic data.

In vitro demonstration of synergy between radionuclide and chemotherapy.

UNLABELLED: Radionuclide therapy is currently used in the treatment of some malignancies, including hepatocellular carcinoma. The effects of external beam radiotherapy are improved by combining it with chemotherapy. The aim of this study was to determine whether such a synergistic effect could be demonstrated in vitro with internal radiation therapy. METHODS: HepG2 cells were cultured from Day 0 to Day 8 under the following conditions: exposure for 4 hr on Day 2 to increasing concentrations of 5-fluorouracil (5FU), doxorubicin or cisplatin (CDDP); exposure from Day 2 to Day 8 to increasing concentrations of 131-iodide; exposure on Day 2 to low-toxicity doses of drugs for 4 hr, followed by exposure to 131I at increasing concentrations; and exposure to increasing concentrations of 131I from Day 2 to Day 8, with exposure for 4 hr on Day 6 to the drugs. Cell toxicity was assessed by enzyme release (lactate dehydrogenase and aspartate aminotransferase) in the culture medium and on cell survival (protein and tetrazolium dye test). All cultures were run in triplicate. RESULTS: A dose- and time-dependent toxicity was demonstrated with doxorubicin and CDDP but not with 5FU. When HepG2 cells were exposed to 131I, the toxicity was rather low, but significant, and was time- and dose-dependent. Treating these cells with combination radiotherapy and chemotherapy resulted in a toxicity that was significantly greater than that with 131I or chemotherapy drugs alone. CONCLUSION: The radiosensitivity of HepG2 cells is low; combining a chemotherapeutic drug with a radiotherapeutic agent improves the radiosensitivity in a synergistic fashion. This combination is thus able to strengthen the therapeutic effect of internal radiation therapy in different malignancies, particularly in hepatocellular carcinoma.

Evaluation of a liver transplant by Tc-99m dimethyl-IDA scintigraphy.

In liver-transplant patients, it is always difficult to differentiate between rejection crises and extrahepatic biliary obstruction on the basis of standard biochemical tests alone. A case is reported of a patient who received a transplant following total hepatectomy performed because of a hepatoma. Scintigraphy with Tc-99m N-(dimethylphenylcarbamoylmethyl)iminodiacetic acid pointed conclusively to an obstructive process, which was confirmed at re-operation.

Traditional management of liver disorders.

Dietary measures have achieved mixed results in the management of liver disorders. Although a high energy diet may shorten the course of viral hepatitis by a relatively small amount, dietary restriction is usually of no benefit in compensated cirrhosis. Restriction of sodium intake to 22 to 60 mol/day leads to resolution of cirrhotic ascites in approximately 20% of patients, and reduces the requirement for diuretics in the remainder. In advanced liver disease, diet plays an important role in the avoidance of portal-systemic encephalopathy (PSE), with the tolerance of most nutrients, most importantly protein, being sharply reduced. Despite the frequent presence of carbohydrate intolerance in liver disease, carbohydrate supplementation may be required to ensure adequate utilisation of the reduced dietary protein intake. Zinc supplementation may also be required in liver cirrhosis to compensate for a deficiency. Bed rest is an important component of the management of acute and chronic liver disorders, together with the avoidance of fatigue. Abstinence from alcohol is required in alcoholic liver disease patients, who should receive parenteral thiamine 100 mg and other vitamin and mineral supplementation as required. Agents acting on the ascending loop of Henle [such as furosemide (frusemide)] or the distal tubule (such as spironolactone) are the diuretics most frequently employed to mobilise ascites in cirrhosis, the latter drug being the more effective in nonazotaemic patients. In the absence of oedema, the diuresis should be restricted to a maximum of 750 ml/day; however, patients with oedema may safely undergo a diuresis of less than or equal to 1.5 L/day. Diuretic therapy is often associated with renal complications, such as azotaemia (usually reversible) and severe hyponatraemia in cirrhotic patients with ascites; spironolactone may produce antiandrogenic adverse effects. Lactulose, used in the treatment of acute and chronic PSE, acts by inhibiting gastrointestinal absorption of ammonia and other toxic nitrogenous substances, and by reducing urea degradation. Other pharmacological treatments, such as branched-chain amino acids and benzodiazepine antagonists have a limited role in the management of PSE. Chronic cholestasis has been treated with cholestyramine and fat-soluble vitamins, whereas ursodeoxycholic acid appears to be a promising agent in the treatment of primary biliary cirrhosis. In chronic hepatitis, the prevention of development of cirrhosis is a primary treatment goal which has been attempted with variable success using antifibrotic drugs such as penicillamine and colchicine.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition of iron overload toxicity in rat hepatocyte cultures by pyoverdin Pf, the siderophore of Pseudomonas fluorescens.

The effect of the pyoverdin Pf (an iron chelating agent isolated and purified from Pseudomonas fluorescens CCM 2798) was studied on iron overloaded rat hepatocyte cultures. Iron overload was obtained by addition of 5-80 microM ferric nitrilotriacetate to the culture medium. Twenty-four hours after iron treatment, a significant increase in aspartate aminotransferase and lactate dehydrogenase in the culture medium was observed. This corresponded to intracellular decrease in the activity of these two enzymes and correlated with a decrease in albumin secretion and an increase in total free malondialdehyde production. The iron toxicity was inhibited by desferrioxamine B. Pyoverdin Pf added to the hepatocyte cultures served as an effective agent to prevent iron toxicity induced in overload. The observed effect of the pyoverdin Pf was as potent as that of desferrioxamine B.

Antiproliferative effect of deferiprone on the Hep G2 cell line.

Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.