D-CECaT

Donfrancesco, Alberto; Deb, Giovanni; Angioni, Adriano; Caniglia, Maurizio; Cozza, Raggaele; Jenkner, Allesandro; Landolfo, Attilio; Boglino, C.; Helson, Lawrence

doi:10.1097/00001813-199306000-00004

Cited by 28 publications

(17 citation statements)

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“…Clinical studies have noted that there is a positive correlation between body iron burden and the risk of developing tumors [34,57]. Although a number of studies have documented that diminishing iron supply to tumor cells could impede tumor growth in experimental models [58,59] and even patients with various cancers [60,61], the molecular bases of the altered iron homeostasis keep largely unexplored in cancers thus far. Recent studies suggest that disordered iron homeostasis in cancers is due to abnormal regulation of hepcidin and ferroportin, both of which have prognostic significance in patients [11,12,62,63].…”

Section: Discussionmentioning

confidence: 99%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

111

136

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Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

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Section: Discussionmentioning

confidence: 99%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

111

136

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“…No effect was observed in a patient with acute nonlymphocytic leukemia who had transfusional iron overload, consistent with iron depletion as a mode of action of DFO. An Italian Phase II study of nine children with neuroblastoma demonstrated responses in 7 of 9 children following treatment with a single course of 150 mg/kg/day DFO given by continuous infusion for 8 h/day for 5 days [97]. This dose, which caused no toxicity, resulted in decrease in bone marrow infiltration as well as a reduction in tumor mass in one patient.…”

Section: Human Studies and Clinical Trialsmentioning

confidence: 99%

The Role of Iron Chelation in Cancer Therapy

Buss¹,

Torti²,

Torti³

2003

CMC

215

216

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This review focuses on advances and strategies in the use of iron chelators as anti-tumor therapies. Although the development of iron chelators for human disease has focused primarily on their use in the treatment of secondary iron overload, chelators may also be useful anti-tumor agents. They can deplete iron or cause oxidative stress in the tumor due to redox perturbations in its environment. Iron chelators have been tested for their anti-tumor activity in cell culture experiments, animal models and human clinical trials. Largely for pragmatic reasons, clinical studies of the anti-tumor activity of iron chelators have generally focused on desferrioxamine (DFO), a drug approved for the treatment of iron overload. These studies have shown that DFO can retard tumor growth in many different experimental contexts. However, the activity of DFO is modest, and advances in the use of chelators as anti-cancer agents will require the development of new chelators based on new paradigms. Examples of iron chelators that have shown promising anti-tumor activity (in various stages of development) include heterocyclic carboxaldehyde thiosemicarbazones, analogs of pyridoxal isonicotinoyl hydrazone, tachpyridine, O-trensox, desferrithiocin, and other natural and synthetic chelators. Apart from their use as single agents, chelators may also synergize with other anti-cancer therapies. The development of chelators as anticancer agents is largely an unexplored field, but one with extraordinary potential to impact human cancer.

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“…1A) (7,8). It has also been demonstrated that DFO possesses anti-proliferative activity, with the chelator having entered clinical trials for cancer treatment (7,9,10). However, the efficacy of DFO is limited by its low lipophilicity and membrane permeability (11,12), and hence, other iron chelators with improved lipophilicity have been developed (8).…”

mentioning

confidence: 99%

Cellular Iron Depletion Stimulates the JNK and p38 MAPK Signaling Transduction Pathways, Dissociation of ASK1-Thioredoxin, and Activation of ASK1

Yu¹,

Richardson

2011

Journal of Biological Chemistry

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The role of signaling pathways in the regulation of cellular iron metabolism is becoming increasingly recognized. Iron chelation is used for the treatment of iron overload but also as a potential strategy for cancer therapy, because iron depletion results in cell cycle arrest and apoptosis. This study examined potential signaling pathways affected by iron depletion induced by desferrioxamine (DFO) or di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). Both chelators affected multiple molecules in the mitogen-activated protein kinase (MAPK) pathway, including a number of dual specificity phosphatases that directly de-phosphorylate MAPKs. Examination of the phosphorylation of major MAPKs revealed that DFO and Dp44mT markedly increased phosphorylation of stress-activated protein kinases, JNK and p38, without significantly affecting the extracellular signal-regulated kinase (ERK). Redox-inactive DFO-iron complexes did not affect phosphorylation of JNK or p38, whereas the redox-active Dp44mT-iron complex significantly increased the phosphorylation of these kinases similarly to Dp44mT alone. Iron or N-acetylcysteine supplementation reversed Dp44mT-induced up-regulation of phospho-JNK, but only iron was able to reverse the effect of DFO on JNK. Both iron chelators significantly reduced ASK1-thioredoxin complex formation, resulting in the increased phosphorylation of ASK1, which activates the JNK and p38 pathways. Thus, dissociation of ASK1 could serve as an important signal for the phosphorylation of JNK and p38 activation observed after iron chelation. Phosphorylation of JNK and p38 likely play an important role in mediating the cell cycle arrest and apoptosis induced by iron depletion.

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D-CECaT

Cited by 28 publications

References 0 publications

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

The Role of Iron Chelation in Cancer Therapy

Cellular Iron Depletion Stimulates the JNK and p38 MAPK Signaling Transduction Pathways, Dissociation of ASK1-Thioredoxin, and Activation of ASK1

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