Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

Raza, Mohsin Ali; Chakraborty, Sankalpa; Choudhury, Monjoy; Ghosh, Prahlad C.; Nag, Alo

doi:10.2174/138920101512141202111915

Cited by 25 publications

(16 citation statements)

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“…These compounds have been used clinically to treat iron-overload conditions ( e.g. haemochromatosis, thalassemia [53] ) and, by limiting iron availability for DNA synthesis, may also be effective anti-neoplastic agents that suppress growth and hyperproliferation of cancer cells [54] . However, our data would indicate that, unless iron chelators are used at concentrations that maintain iron stores within tight physiological limits or offer selective toxicity towards cancer cells, they may also inadvertently compromise function of normal cells through their effect not just on the mTOR pathway, but upon expression/activity of other proteins with key roles in signalling, metabolism and cell cycle biology.…”

Section: Discussionmentioning

confidence: 99%

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

Watson

Lipina

McArdle

et al. 2016

Cellular Signalling

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Iron is an indispensable micronutrient that regulates many aspects of cell function, including growth and proliferation. These processes are critically dependent upon signalling via the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Herein, we test whether iron depletion induced by cell incubation with the iron chelator, deferoxamine (DFO), mediates its effects on cell growth through mTORC1-directed signalling and protein synthesis. We have used Caco-2 cells, a well-established in vitro model of human intestinal epithelia. Iron depletion increased expression of iron-regulated proteins (TfR, transferrin receptor and DMT1, divalent metal transporter, as predicted, but it also promoted a marked reduction in growth and proliferation of Caco-2 cells. This was strongly associated with suppressed mTORC1 signalling, as judged by reduced phosphorylation of mTOR substrates, S6K1 and 4E-BP1, and diminished protein synthesis. The reduction in mTORC1 signalling was tightly coupled with increased expression and accumulation of REDD1 (regulated in DNA damage and development 1) and reduced phosphorylation of Akt and TSC2. The increase in REDD1 abundance was rapidly reversed upon iron repletion of cells but was also attenuated by inhibitors of gene transcription, protein phosphatase 2A (PP2A) and by REDD1 siRNA — strategies that also antagonised the loss in mTORC1 signalling associated with iron depletion. Our findings implicate REDD1 and PP2A as crucial regulators of mTORC1 activity in iron-depleted cells and indicate that their modulation may help mitigate atrophy of the intestinal mucosa that may occur in response to iron deficiency.

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Section: Discussionmentioning

confidence: 99%

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

Watson

Lipina

McArdle

et al. 2016

Cellular Signalling

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“…However, many clinical trials have failed to show any benefits of the use of these chelators in these diseases [ 146 ]. Compared to the efficacy of iron chelators for cancer, some clinical evidence shows that iron chelators also have obvious toxic side effects [ 147 , 148 ]. A recent review also showed concerns about clinical efficacy and side effects of iron chelators for iron storage diseases [ 149 ].…”

Section: Therapeutic Opportunities For Cancer Based On Altered Iromentioning

confidence: 99%

Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer

Zhou

Zhao

Zhang

et al. 2018

IJMS

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Iron is an essential element for the growth and proliferation of cells. Cellular iron uptake, storage, utilization and export are tightly regulated to maintain iron homeostasis. However, cellular iron metabolism pathways are disturbed in most cancer cells. To maintain rapid growth and proliferation, cancer cells acquire large amounts of iron by altering expression of iron metabolism- related proteins. In this paper, normal cellular iron metabolism and the alterations of iron metabolic pathways in cancer cells were summarized. Therapeutic strategies based on targeting the altered iron metabolism were also discussed and disrupting redox homeostasis by intracellular high levels of iron provides new insight for cancer therapy. Altered iron metabolism constitutes a promising therapeutic target for cancer therapy.

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“…Moreover, these targets could be used for the development of new diagnostic tools able to provide an insight into the frequency of CSC within the tumor. Based on evidences obtained from both epidemiological and molecular studies, new insights are emerging linking the presence of excess iron and altered iron metabolism to cancer [14, 15]. Recently, Schonberg et al [16] have demonstrated an enhanced iron scavenging ability in CSC of glioblastoma multiforme, due to a significant overexpression of the transferrin receptor (TfR) and a consequent increase in transferrin uptake, which is indicative of increased tumorigenicity.…”

Section: Introductionmentioning

confidence: 99%

L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

et al. 2016

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A growing body of evidence suggests that cancer stem cells (CSC) have the unique biological properties necessary for tumor maintenance and spreading, and function as a reservoir for the relapse and metastatic evolution of the disease by virtue of their resistance to radio- and chemo-therapies. Thus, the efficacy of a therapeutic approach relies on its ability to effectively target and deplete CSC. In this study, we show that CSC-enriched tumorspheres from breast cancer cell lines display an increased L-Ferritin uptake capability compared to their monolayer counterparts as a consequence of the upregulation of the L-Ferritin receptor SCARA5. L-Ferritin internalization was exploited for the simultaneous delivery of Curcumin, a natural therapeutic molecule endowed with antineoplastic action, and the MRI contrast agent Gd-HPDO3A, both entrapped in the L-Ferritin cavity. This theranostic system was able to impair viability and self-renewal of tumorspheres in vitro and to induce the regression of established tumors in mice. In conclusion, here we show that Curcumin-loaded L-Ferritin has a strong therapeutic potential due to the specific targeting of CSC and the improved Curcumin bioavailability, opening up the possibility of its use in a clinical setting.

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Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

Cited by 25 publications

References 0 publications

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

Iron depletion suppresses mTORC1-directed signalling in intestinal Caco-2 cells via induction of REDD1

Alterations in Cellular Iron Metabolism Provide More Therapeutic Opportunities for Cancer

L-Ferritin targets breast cancer stem cells and delivers therapeutic and imaging agents

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