Iron as a target of chemoprevention for longevity in humans

Abstract

Iron is universally abundant and no life can exist without it. However, iron levels should be maintained within a narrow range. Iron deficiency causes anaemia, whereas excessive iron increases cancer risk, presumably by free radical generation. Several pathological conditions such as genetic haemochromatosis, chronic viral hepatitis B and C, conditions related to asbestos fibre exposure and ovarian endometriosis have been recognized as iron overload-associated conditions that also increase human cancer risks. Iron's carcinogenicity has been documented in animal experiments. Surprisingly, these studies have revealed that the homozygous deletion of CDKN2A/2B is a major hallmark of iron-induced carcinogenesis. Recently, the hormonal regulation of iron metabolism has been elucidated. A commonly hypothesized mechanism may be the lack of any iron disposal pathway other than for bleeding and a mechanism of iron re-uptake as catechol chelate has been discovered. Iron overload in neurons via the ferroportin block may play a role in Alzheimer's disease. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy was associated with decreased cancer risks in a general population. Given that the required amounts of iron decrease during ageing, the fine control of body iron stores would be a wise strategy for chemoprevention of several diseases.     

Cancer cells with irons in the fire

Iron is essential for the growth and proliferation of cells, as well as for many biological processes that are important for the maintenance and survival of the human body. However, excess iron is associated with the development of cancer and other pathological conditions, due in part to the pro-oxidative nature of iron and its damaging effects on DNA. Current studies suggest that iron depletion may be beneficial for patients that have diseases associated with iron overload or other iron metabolism disorders that may increase the risk for cancer. On the other hand, studies suggest that cancer cells are more vulnerable to the effects of iron depletion and oxidative stress in comparison to normal cells. Therefore, cancer patients might benefit from treatments that alter both iron metabolism and oxidative stress. This review highlights the pro-oxidant effects of iron, the relationship between iron and cancer development, the vulnerabilities of the iron-dependent cancer phenotype, and how these characteristics may be exploited to prevent or treat cancer.     

Iron and genome stability: An update

Iron is an essential micronutrient which is required in a relatively narrow range for maintaining metabolic homeostasis and genome stability. Iron participates in oxygen transport and mitochondrial respiration as well as in antioxidant and nucleic acid metabolism. Iron deficiency impairs these biological pathways, leading to oxidative stress and possibly carcinogenesis. Iron overload has been linked to genome instability as well as to cancer risk increase, as seen in hereditary hemochromatosis. Iron is an extremely reactive transition metal that can interact with hydrogen peroxide to generate hydroxyl radicals that form the 8-hydroxy-guanine adduct, cause point mutations as well as DNA single and double strand breaks. Iron overload also induces DNA hypermethylation and can reduce telomere length. The current Recommended Dietary Allowances (RDA) for iron, according with Institute of Medicine Dietary Reference Intake (DRI), is based in the concept of preventing anemia, and ranges from 7mg/day to 18mg/day depending on life stage and gender. Pregnant women need 27mg/day. The maximum safety level for iron intake, the Upper Level (UL), is 40-45mg/day, based on the prevention of gastrointestinal distress associated to high iron intakes. Preliminary evidence indicates that 20mg/day iron, an intake slightly higher than the RDA, may reduce the risk of gastrointestinal cancer in the elderly as well as increasing genome stability in lymphocytes of children and adolescents. Current dietary recommendations do not consider the concept of genome stability which is of concern because damage to the genome has been linked to the origin and progression of many diseases and is the most fundamental pathology. Given the importance of iron for homeostasis and its potential influence over genome stability and cancer it is recommended to conduct further studies that conclusively define these relationships.     

Iron and carcinogenesis: from Fenton reaction to target genes

Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metal ion in our body, may work as a catalyst for the generation of ROS in pathological conditions. In the past few years, there have been great advances in the understanding of iron metabolism. These include the discoveries of iron transporters and the gene responsible for hereditary hemochromatosis. Iron overload has been shown to be associated with carcinogenesis. We recently identified the major target genes (p16(INK4A) and p15(INK4B) tumor suppressor genes, which encode cyclin-dependent kinase inhibitors) in a ferric nitrilotriacetate-induced rat renal carcinogenesis model, in which the Fenton reaction is induced in the renal proximal tubules. Allelic loss of the p16 gene occurs early in carcinogenesis and specifically at the p16 loci as compared with other tumor suppressor genes. This led to the novel concept of 'genomic sites vulnerable to the Fenton reaction'. Here, recent new findings on iron metabolism are reviewed and the concept of the vulnerable sites explored. More effort to link iron metabolism with human carcinogenesis is anticipated.     

Iron: Key player in cancer and cell cycle?

BackgroundIron is an essential element for growth and metabolic activities of all living organisms but remains in its oxyhydroxide ferric ion form in the surrounding. Unavailability of iron in soluble ferrous form led to development of specific pathways and machinery in different organisms to make it available for use and maintain its homeostasis. Iron homeostasis is essential as under different circumstances iron in excess as well as deprivation leads to different pathological conditions in human.ObjectiveThis review highlights the current findings related to iron excess as well as deprivation with regards to cellular proliferation.ConclusionsIron excess is extensively associated with different types of cancers viz. colorectal cancer, breast cancer etc. by producing an oxidative stressed condition and alteration of immune system. Ironically its deprivation also results in anaemic conditions and leads to cell cycle arrest at different phases with mechanism yet to be explored. Iron deprivation arrests cell cycle at G1/S and in some cases at G2/M checkpoints resulting in growth arrest. However, in some cases iron overload arrests cell cycle at G1 phase by blocking certain signalling pathways. Certain natural and synthetic iron chelators are being explored from few decades to combat diseases caused by alteration in iron homeostasis.     

Different physiological responses of cyanobacteria to ultraviolet‐B radiation under iron‐replete and iron‐deficient conditions: Implications for underestimating the negative effects of UV‐B radiation

Iron deficiency has been considered one of the main limiting factors of phytoplankton productivity in some aquatic systems including oceans and lakes. Concomitantly, solar ultraviolet‐B radiation has been shown to have both deleterious and positive impacts on phytoplankton productivity. However, how iron‐deficient cyanobacteria respond to UV‐B radiation has been largely overlooked in aquatic systems. In this study, physiological responses of four cyanobacterial strains (Microcystis and Synechococcus), which are widely distributed in freshwater or marine systems, were investigated under different UV‐B irradiances and iron conditions. The growth, photosynthetic pigment composition, photosynthetic activity, and nonphotochemical quenching of the different cyanobacterial strains were drastically altered by enhanced UV‐B radiation under iron‐deficient conditions, but were less affected under iron‐replete conditions. Intracellular reactive oxygen species (ROS) and iron content increased and decreased, respectively, with increased UV‐B radiation under iron‐deficient conditions for both Microcystis aeruginosa FACHB 912 and Synechococcus sp. WH8102. On the contrary, intracellular ROS and iron content of these two strains remained constant and increased, respectively, with increased UV‐B radiation under iron‐replete conditions. These results indicate that iron‐deficient cyanobacteria are more susceptible to enhanced UV‐B radiation. Therefore, UV‐B radiation probably plays an important role in influencing primary productivity in iron‐deficient aquatic systems, suggesting that its effects on the phytoplankton productivity may be underestimated in iron‐deficient regions around the world.     

铁与2型糖尿病发病的最新进展

糖尿病对人类健康的威胁日益加重,近年来大量的实验、临床及流行病学资料显示体内铁过载与糖尿病发生存在密切关联。作为机体必需的营养元素,铁在机体组织中的稳态平衡对维持正常的生理功能至关重要。同时铁还是一种极强的促氧化剂,机体铁含量升高往往导致氧化压力增强,进而加大罹患2型糖尿病的风险;膳食中血红素铁摄入量增加以及机体铁代谢紊乱都可能导致2型糖尿病及其并发症发生。此外,其他胰岛素抵抗疾病如代谢综合征、妊娠糖尿病以及多囊卵巢综合征都与铁过载呈显著关联,过量铁是诱发这些疾病的主要原因,并直接导致胰岛素抵抗。治疗中可通过铁螯合剂的使用来有效降低机体铁水平,并改善胰岛素抵抗。这些研究成果为2型糖尿病的干预治疗提供了新思路。对铁代谢与2型糖尿病及其并发症的最新研究做简要综述。     

Iron chelators can protect against oxidative stress through ferryl heme reduction

Iron chelators such as desferrioxamine have been shown to ameliorate oxidative damage in vivo. The mechanism of this therapeutic action under non-iron-overload conditions is, however, complex, as desferrioxamine has properties that can impact on oxidative damage independent of its capacity to act as an iron chelator. Desferrioxamine can act as a reducing agent to remove cytotoxic ferryl myoglobin and hemoglobin and has recently been shown to prevent the formation of a highly cytotoxic heme-to-protein cross-linked derivative of myoglobin. In this study we have examined the effects of a wide range of iron chelators, including the clinically used hydroxypyridinone CP20 (deferriprone), on the stability of ferryl myoglobin and on the formation of heme-to-protein cross-linking. We show that all hydroxypyridinones, as well as many other iron chelators, are efficient reducing agents of ferryl myoglobin. These compounds are also effective at preventing the formation of cytotoxic derivatives of myoglobin such as heme-to-protein cross-linking. These results show that the use of iron chelators in vivo may ameliorate oxidative damage under conditions of non-iron overload by at least two mechanisms. The antioxidant effects of chelators in vivo cannot, therefore, be attributed solely to iron chelation.     

The role of iron in type 2 diabetes in humans

The role of micronutrients in the etiology of type 2 diabetes is not well established. Several lines of evidence suggest that iron play may a role in the pathogenesis of type 2 diabetes. Iron is a strong pro-oxidant and high body iron levels are associated with increased level of oxidative stress that may elevate the risk of type 2 diabetes. Several epidemiological studies have reported a positive association between high body iron stores, as measured by circulating ferritin level, and the risk of type 2 diabetes and of other insulin resistant states such as the metabolic syndrome, gestational diabetes and polycystic ovarian syndrome. In addition, increased dietary intake of iron, especially that of heme iron, is associated with risk of type 2 diabetes in apparently healthy populations. Results from studies that have evaluated the association between genetic mutations related to iron metabolism have been inconsistent. Further, several clinical trials have suggested that phlebotomy induced reduction in body iron levels may improve insulin sensitivity in humans. However, no interventional studies have yet directly evaluated the effect of reducing iron intake or body iron levels on the risk of developing type 2 diabetes. Such studies are required to prove the causal relationship between moderate iron overload and diabetes risk.     

Nitric oxide and iron: effect of iron overload on nitric oxide production in endotoxemia

The amount of iron within the cell is carefully regulated in order to provide an adequate level of micronutrient while preventing its accumulation and toxicity. Iron excess is believed to generate oxidative stress, understood as an increase in the steady-state concentration of oxygen radical intermediates. Nitric oxide (NO) is an inorganic free-radical gaseous molecule which has been shown over the last decade to play an unprecedented variety of roles in biological systems. The effect of nitrogen reactive species may explain the iron sequestration pattern that characterizes macrophages under inflammatory conditions. From a patho-physiological viewpoint, further studies are required to assess the usefulness of this mechanism to minimize formation and release of free radicals in diseased tissues. However, contrary to the deleterious effects of the reactive nitrogen oxide species formed from either NO/O(2) and NO/O(2)(-), it has been pointed out that NO shows antioxidant properties. A number of studies have described the complex relationships between iron and NO, but controversy remains as to the influence and significance of iron on inflammatory NO production. To explore the initial steps of the effects triggered by LPS administration in the presence of excess iron, male Wistar rats were treated with: lipopolysaccharide from Escherichia coli (serotype 0127:B8) (LPS); iron-dextran; or iron-dextran plus LPS and liver samples were taken after 6 h. EPR spectra of NO-Hb in the venous blood were determined at 77 K. Iron-dextran administered to rats intraperitoneally resulted predominantly in iron uptake by the liver Kupffer cells and led to an increased NO level in blood in the presence of LPS. Further studies will be required to assess the complex role of the Kupffer cells on iNOS induction and NO production.     

Studies on the Hemophilus group of organisms; quantitative aspects of growth on various porphin compounds

The porphin requirements of the Hemophilus organisms have been studied. Organisms of the parainfluenzae group show quantitative differences in their ability to synthesize heme. The ability of the parainfluenzae organisms to grow appears to depend on the rate with which they synthesize heme and in part at least on the properties of the medium to protect the heme from peroxidative breakdown. Quantitative studies of the growth of H. influenzae Turner on various iron porphins have been made. Iron protoporphin gives greatest growth when supplied in excess, although iron mesoporphin appears more efficient at lower concentrations. Iron deutero- and iron hematoporphin are much less effective. This suggests that although the vinyl groups are not essential for growth of the Turner organism they may be required for some particular enzymes which aid in attaining maximum growth. A number of substances potentiate the growth-promoting properties of iron porphins. These substances include reducing agents and agents which destroy H(2)O(2). E. influenzae Turner appears to require heme for anaerobic as well as aerobic growth. The possibility of an essential heme enzyme functioning under anaerobic conditions must therefore be considered.     

Evidence that iron-overload promotes 7, 12-dimethylbenz(a)anthracene-induced skin tumorigenesis in mice

Summary

Iron overload is known to occur in West European and American populations due to the consumption of an iron-rich diet. There are also genetic disorders which lead to body iron overload. It has been shown that iron overload predisposes humans to an increased risk of cancer. In experimental animals, iron overload is known to enhance intestinal, colon, hepatic, pulmonary and mammary carcinogenesis. However, the mechanism by which iron overload enhances chemically-induced carcinogenesis is not known. In this study, we show that iron overload acts as a mild tumor promoter in mouse skin. Female albino swiss mice were given 1 mg iron/mouse parenterally for 2 weeks to induce iron overload. These animals showed a three-fold increase in cutaneous iron concentration as compared to normal mice. Tumors were initiated by topically applying 7,12-dimethylbenz(a)anthracene (DMBA). Appearance of the first tumor (latency period), percent tumor incidence and number of tumors/mouse were recorded. When compared to the control group, iron overload mice showed an increased incidence of tumors, from 25%-55% by week 20, and tumors appeared 4 weeks earlier. The number of tumors per mouse was four-fold higher in the iron overload group. The induction of cutaneous ornithine decarboxylase (ODC) activity and [³H]thymidine incorporation in cutaneous DNA were higher in iron overload groups as compared to normal control animals. Similar to other oxidant tumor promoters, iron overload enhanced cutaneous lipid peroxidation and xanthine oxidase activity and decreased catalase activity. Our results indicate that iron overload exerts a mild tumor promoting activity in mouse skin. Our data also show that oxidative stress generated by iron overload plays an important role in the augmentation of cutaneous tumorigenesis. These data may also have implications for the enhanced risk of cancer-induction following UVB exposure of human populations with iron overload.     

Topical applications of iron chelators in photosensitization.

Generation of the reactive oxygen species (ROS) in skin by exposure to ultraviolet (UV) radiation induces a number of cutaneous pathologies such as skin cancer, photosensitization, and photoaging among others. Skin iron catalyzes UV generation of ROS. Topical application of iron chelators reduces erythema, epidermal and dermal hypertrophy, wrinkle formation, tumour appearance. It has been proposed that iron chelators can be useful agents against damaging effects of both short- and long-term UV exposure. A better understanding of the action mechanisms of iron chelators, might be useful to developing effective anticancer and antiphotoaging cosmetic products. Iron chelators may lead to accumulation of protoporphyrin IX (PpIX), a strong photosensitizer. The action of iron chelators in skin, related to PpIX increase has not yet been thoroughly studied. Therefore, we have investigated the formation of PpIX in normal mouse skin after topical application of creams containing metal chelators. The amount and distribution of porphyrins formed was determined by means of non-invasive fluorescence spectroscopy. Deferoxamine (DF), ethylenediaminetetraacetic acid (EDTA), 1,2-diethyl-3-hydroxypyridin-4-one (CP94), but not meso-2,3-dimercaptosuccinic acid (DMSA), caused increased accumulation of endogenous porphyrins in the skin. Fluorescence excitation and emission spectroscopy confirmed that PpIX was the main fluorescent species. The amount of PpIX accumulated in skin under the present conditions was not large enough to produce any significant erythema after light exposure. Further studies are needed to evaluate the role of PpIX induced by iron chelators used, against photoaging and cancer prevention.     

Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease

A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pK(a), pFe(3+) and logP) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.     

Iron loading: a risk factor for osteoporosis

Iron loaded persons are at increased risk for infection, neoplasia, arthropathy, cardiomyopathy and an array of endocrine and neurodegenerative diseases. This report summarizes evidence of increased risk of iron loading for osteoporosis. Iron suppresses bone remodeling apparently by decreasing osteoblast formation and new bone synthesis. Low molecular mass iron chelators as well as a natural protein iron chelator, lactoferrin, may be useful in prevention of osteoporosis.     

Hemochromatosis heterozygotes may constitute a radiation-sensitive subpopulation

A primary mechanism of radiation-induced DNA damage is by generation of free radicals. Chronically increased oxidative stress from elevated levels of iron in the body may increase radiation sensitivity by decreasing cellular oxygen radical scavenging capability. Hemochromatosis heterozygotes have elevated body iron. Low-level radiation sensitization by iron may be particularly pertinent for risk of breast cancer. Since 10% of the population appears to be heterozygous for the hemochromatosis gene, a radiosensitizing effect would have pervasive implications.     

Ethanol-induced iron mobilization: role of acetaldehyde-aldehyde oxidase generated superoxide

Superoxide radicals, a species known to mobilize ferritin iron, and their interaction with catalytic iron have been implicated in the pathogenesis of alcohol-induced liver injury. The mechanism(s) by which ethanol metabolism generates free radicals and mobilizes catalytic iron, however, is not fully defined. In this investigation the role of hepatic aldehyde oxidase in the mobilization of catalytic iron from ferritin was studied in vitro. Iron mobilization due to the metabolism of ethanol to acetaldehyde by alcohol dehydrogenase was increased 100% by the addition of aldehyde oxidase. Iron release was favored by low pH and low oxygen concentration. Mobilization of iron due to acetaldehyde metabolism by aldehyde oxidase was completely inhibited by superoxide dismutase but not by catalase suggesting that superoxide radicals mediate mobilization. Acetaldehyde-aldehyde oxidase mediated reduction of ferritin iron was facilitated by incubation with menadione, an electron acceptor for aldehyde oxidase. Mobilization of ferritin iron due to the metabolism of acetaldehyde by aldehyde oxidase may be a fundamental mechanism of alcohol-induced liver injury.     

Iron Enhancement of Ascorbate Toxicity

Iron has been shown to enhance ascorbate-induced damage to both acetylcholine esterase and E. coli B in a manner analogous to previous studies with ascorbate and copper ions. It is suggested that the mechanism of damage entails interaction of iron with biological macromolecules, followed by its reduction by ascorbate. Subsequently, the iron (11) could participate in generating hydroxyl radicals from hydrogen peroxide via the Fenton reaction, which in turn, could damage biomolecules in a site-specific and multiple hit fashion. The high abundance of iron in biological systems, especially in certain storage disorders, may indicate an important toxicological role of the combination of iron and ascorbate.     

Iron Enhancement of Ascorbate Toxicity

Iron has been shown to enhance ascorbate-induced damage to both acetylcholine esterase and E. coli B in a manner analogous to previous studies with ascorbate and copper ions. It is suggested that the mechanism of damage entails interaction of iron with biological macromolecules, followed by its reduction by ascorbate. Subsequently, the iron (11) could participate in generating hydroxyl radicals from hydrogen peroxide via the Fenton reaction, which in turn, could damage biomolecules in a site-specific and multiple hit fashion. The high abundance of iron in biological systems, especially in certain storage disorders, may indicate an important toxicological role of the combination of iron and ascorbate.     

A primer for predicting risk of disease in HFE-linked hemochromatosis

Since the discovery of the hemochromatosis gene (HFE) in 1996, there has been increasing interest in diagnostic testing for the C282Y and H63D mutations. The high frequency of these two alleles and their incomplete penetrance in homozygotes and compound heterozygotes make genetic counseling for hemochromatosis different from some other autosomal recessive conditions in that parents and children may also be at risk for iron overload, while homozygotes may remain asymptomatic. We provide a guideline for genetic counseling in HFE-linked hemochromatosis based on the genetic probability of inheriting HFE mutations and known information about expression of iron overload in various HFE genotypes. Genetic probabilities were based on allele frequencies derived from large population studies and Hardy-Weinberg equilibrium estimates. Expression of iron overload in those of various genotypes was based on available estimates of serum ferritin from population screening studies. Estimates for the likelihood of clinical iron overload requiring follow-up screening or treatment are provided by gender and genotype. The probability of inheriting HFE mutations and developing iron overload can be estimated in family members of a proband with HFE mutations. Many C282Y homozygotes will not have clinical iron overload. The risk is highest in men and their C282Y homozygous brothers and significantly lower in homozygous women. Iron overload is uncommon in compound heterozygotes and H63D homozygotes.