Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect

International audienceTumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cance

Transcripts of ceruloplasmin but not hepcidin, both major iron metabolism genes, exhibit a decreasing pattern along portocentral axis of mouse liver

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Mouse genetic background impacts both on iron and non-iron metals parameters and on their relationships

International audienceIron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolis

Surcharges en fer génétiques : atypies de l'acéruloplasminémie héréditaire

National audienceThe knowledge in iron metabolism obtained in the last 20 years has made it possible to draw up an understandable picture of the systemic metabolism of iron. This is mainly due to the identification of proteins playing a major role in the systemic distribution of iron. However, some rare iron metabolism diseases, including Hereditary Aceruloplasminemia (AH), are not fully understood. AH is a genetic disease of recessive inheritance, linked to mutations within the gene encoding the ceruloplasmin, a multicopper oxidase. Mutations lead to the loss of the ferroxidase activity of the protein and favors the development of a parenchymal iron overload, affecting the liver, the pancreas, but also, a unique fact in systemic iron overload disease, the brain. The peculiarity of the hepatosplenic phenotype, which surprisingly spares hepatic and spleen macrophages regarding the potential biological role of ceruloplasmin together with the existence of a cerebral iron overload, certainly account for the existence of complementary mechanisms contributing to the disease. Their understanding will make it possible to improve the follow-up of patients and to obtain new knowledge on iron metabolism for the management of other diseases in which the abnormal accumulation of iron in the brain plays a determining role.Les connaissances obtenues dans les 20 dernières années ont permis de dresser un tableau compréhensible du métabolisme du fer, notamment du fait de la mise en évidence de protéines majeures permettant la circulation systémique du fer. Cependant, certaines pathologies rares du métabolisme du fer, dont l'acéruloplasminémie héréditaire (AH), pointent l'existence de mécanismes complémentaires potentiels encore non identifiés. L'AH est une pathologie génétique de transmission récessive liée à des mutations touchant le gène codant la céruloplasmine. Les mutations conduisent, du fait de la perte de l'activité ferroxidasique de la protéine, au développement d'une surcharge en fer parenchymateuse, touchant le foie, le pancréas, mais aussi, fait unique dans une pathologie de surcharge en fer systémique, le cerveau. La particularité du phénotype hépatosplénique et l'existence d'une surcharge en fer cérébrale rendent certainement compte de l'existence de mécanismes complémentaires concourant à la pathologie. Leur compréhension permettra de mieux prendre en charge ces patients et de disposer de nouvelles données pour la prise en charge d'autres pathologies dont celles au cours desquelles l'accumulation de fer dans le cerveau joue un rôle déterminant

Hemochromatoses

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Iron metabolism and related genetic diseases: a cleared land, keeping mysteries

International audienceBody iron has a very close relationship with the liver. Physiologically, the liver synthetizes transferrin, in charge of blood iron transport, ceruloplasmin, acting through its ferroxidase activity, and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution

Iron and the liver: update 2008

International audienceThe cross-talk which has taken place in recent years between clinicians and scientists has resulted in a greater understanding of iron metabolism with the discovery of new iron-related genes including the hepcidin gene which plays a critical role in regulating systemic iron homeostasis. Consequently, the distinction between (a) genetic iron-overload disorders including haemochromatosis related to mutations in the HFE, hemojuvelin, transferrin receptor 2 and hepcidin genes and (b) non-haemochromatotic conditions related to mutations in the ferroportin, ceruloplasmin, transferrin and di-metal transporter 1 genes, and (c) acquired iron-overload syndromes has become easier. However, major challenges still remain which include our understanding of the regulation of hepcidin production, the identification of environmental and genetic modifiers of iron burden and organ damage in iron-overload syndromes, especially HFE haemochromatosis, indications regarding the new oral chelator, deferasirox, and the development of new therapeutic tools interacting with the regulation of iron metabolism

Miscellaneous non-inflammatory musculoskeletal conditions. Haemochromatosis: the bone and the joint.

International audienceGenetic haemochromatosis is a hereditary disease characterised by tissue iron overload. In Caucasians it is most often due to homozygous C282Y HFE gene mutation, but other genes may be involved. Without treatment by venesections, patients can develop life-threatening visceral damage such as liver cirrhosis and carcinoma, diabetes or heart failure. This treatment has been remarkably successful in preventing these complications, but patients survive with other symptoms of the disease susceptible to impair, sometimes seriously, their quality of life. This is the case of arthropathy and osteoporosis complicating haemochromatosis. In this chapter, focus has been placed on the rheumatological complications of genetic haemochromatosis

The interaction of iron and the genome: For better and for worse

International audienceIron, as an essential nutrient, and the DNA, as the carrier of genetic information which is physically compacted into chromosomes, are both needed for normal life and well-being. Therefore, it is not surprising that close interactions exist between iron and the genome. On the one hand, iron, especially when present in excess, may alter genome stability through oxidative stress, and may favor cell cycle abnormalities and the development of malignant diseases. The genome also receives a feedback signal from the systemic iron status, leading to promotion of expression of genes that regulate iron metabolism. Conversely, on the other hand, DNA mutations may cause genetic iron-related diseases such as hemochromatosis, archetype of iron-overload diseases, or refractory iron deficiency anemia (IRIDA). © 2017 Elsevier B.V

Métabolisme du fer : impact de l'hypoactivité et mécanismes sous-jacents

National audienceEn situation d’impesanteur ou d’alitement, astronautes et patients hospitalisés subissent une réduction considérable de leur activité musculaire, qualifiée d’hypoactivité, qui impacte directement leur état de santé. En raison de son implication dans le transport et le stockage tissulaire de l’oxygène, tout comme dans le métabolisme énergétique, le fer et son métabolisme pourraient jouer un rôle essentiel dans certaines des altérations physiologiques associées à l’hypoactivité. Sa redistribution de manière anormale pourrait, en effet, contribuer à l’anémie et au stress oxydant hautement délétère observé dans certains organes en situation d’hypoactivité (c.-à-d., os et muscle squelettique). Dans ce contexte, l’objectif de cette revue de synthèse est de présenter les connaissances actuelles concernant la régulation du métabolisme du fer en réponse à l’hypoactivité, et d’ouvrir des pistes de réflexion pour améliorer la prise en charge nutritionnelle des astronautes et des patients alités