Iron Chelation in the Treatment of Cancer: A New Role for Deferasirox?

Bedford, Matthew; Ford, Samuel J.; Horniblow, Richard D.; Iqbal, Tariq; Tselepis, Chris

doi:10.1002/jcph.113

Cited by 80 publications

(59 citation statements)

References 70 publications

(106 reference statements)

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“…Having precise knowledge of the biosynthetic pathways of siderophores can be a true asset in biotechnology. Indeed, because of the strong metal chelating properties of these compounds and their importance in bacterial iron homeostasis, siderophores have many applications in either biomedical (Bedford et al ., ; Mislin and Schalk, ; Schalk and Mislin, ; Schalk, ) or bioremediation (Cornu et al ., ; Ferret et al ., ; Hazotte et al ., ) approaches.…”

Section: Discussionmentioning

confidence: 99%

An overview of siderophore biosynthesis among fluorescent Pseudomonads and new insights into their complex cellular organization

Schalk

Rigouin

Godet

2020

Environmental Microbiology

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Summary Siderophores are iron‐chelating molecules produced by bacteria to access iron, a key nutrient. These compounds have highly diverse chemical structures, with various chelating groups. They are released by bacteria into their environment to scavenge iron and bring it back into the cells. The biosynthesis of siderophores requires complex enzymatic processes and expression of the enzymes involved is very finely regulated by iron availability and diverse transcriptional regulators. Recent data have also highlighted the organization of the enzymes involved in siderophore biosynthesis into siderosomes, multi‐enzymatic complexes involved in siderophore synthesis. An understanding of siderophore biosynthesis is of great importance, as these compounds have many potential biotechnological applications because of their metal‐chelating properties and their key role in bacterial growth and virulence. This review focuses on the biosynthesis of siderophores produced by fluorescent Pseudomonads, bacteria capable of colonizing a large variety of ecological niches. They are characterized by the production of chromopeptide siderophores, called pyoverdines, which give the typical green colour characteristic of fluorescent pseudomonad cultures. Secondary siderophores are also produced by these strains and can have highly diverse structures (such as pyochelins, pseudomonine, yersiniabactin, corrugatin, achromobactin and quinolobactin).

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Section: Discussionmentioning

confidence: 99%

An overview of siderophore biosynthesis among fluorescent Pseudomonads and new insights into their complex cellular organization

Schalk

Rigouin

Godet

2020

Environmental Microbiology

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“…A number of in vitro and in vivo studies have demonstrated that DFX has powerful antiproliferative effects [17]. To our knowledge, there have been no studies investigating the effects of DFX against pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

et al. 2016

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BackgroundIron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.MethodsThe effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.ResultsDFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.ConclusionsDFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.

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“…However, misregulation of this system would elicit detrimental effects on cells, such as the oncogenic effect of intracellularly retained free iron [1,2]. Deregulated systemic iron homeostasis contributes to cancer risk and progression [2,3].…”

Section: Introductionmentioning

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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Iron Chelation in the Treatment of Cancer: A New Role for Deferasirox?

Cited by 80 publications

References 70 publications

An overview of siderophore biosynthesis among fluorescent Pseudomonads and new insights into their complex cellular organization

An overview of siderophore biosynthesis among fluorescent Pseudomonads and new insights into their complex cellular organization

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

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