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Iron as a Central Player and Promising Target in Cancer Progression

Michaela Jung, Christina Mertens, Elisa Tomat and 1 more

International Journal of Molecular Sciences · 2019 · Review · CC BY

doi:10.3390/ijms20020273

Abstract

Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Iron and Cancer

Iron is the most abundant element by mass on the Earth and is a growth-limiting factor for virtually all organisms. Considering the poor bioavailability of iron, the interplay of different proteins involved in iron import, storage, and export has to be tightly regulated, as there is no excretory route for excess iron. The ability of iron to get oxidized or reduced enables iron to take part in free radical generating reactions. Among them is the Fenton reaction; ferrous iron donates an electron to hydrogen peroxide to produce the hydroxyl radical, a highly reactive oxygen species. As a result, iron is potentially mutagenic by causing DNA strand breaks, which provokes cellular transformations, or induces protein as well as lipid modifications within malignant cells. In turn, this may cause a more aggressive tumor cell behavior. Accumulation of iron-dependent lipid modifications promotes a specific form of cell death, known as ferroptosis. This is a distinct type of cell death compared to apoptosis, necrosis, or autophagy. During ferroptosis, a lethal metabolic imbalance arises from glutathione depletion, which inactivates the lipid repair enzyme glutathione-dependent peroxidase 4, GPX4, with the subsequent accumulation of lipid peroxides. Nevertheless, mammalian cells require sufficient amounts of iron to satisfy metabolic needs and accomplish specialized functions. Only to mention a few, DNA polymerases and helicases contain iron-sulfur groups that rely on iron as essential co-factors. In addition, cellular iron availability not only controls mitochondrial respiration, but also affects citric acid cycle enzymes.

The malignant cancer phenotype is often found in association with a deregulated iron homeostasis, particularly the expression of iron-regulated genes that fuel their higher metabolic iron demands needed for division, growth, and survival. This surplus of iron is needed not only both during early steps of tumor development, e.g., enhanced survival and proliferation of transformed cells, but also during late stages to promote the metastatic cascade. Here, iron is crucial in remodeling the extracellular matrix and increasing the motility and invasion of cancer cells. A dysfunctional or deregulated iron metabolism in cancer patients often results in a decreased red blood cell (RBC) count and anemia is detected in approximately 40–70% of all cancer patients. Furthermore, cancer-induced anemia as well as inflammation-associated anemia is characterized by reduced erythropoiesis. Mechanistically, cancer-induced anemia is caused by the secretion of inflammatory factors, such as tumor necrosis factor (TNF)-α and interleukin-6 (IL-6). They inhibit erythropoiesis due to iron restriction in the reticuloendothelial system. The role of iron in cancer progression was also documented by experimental animal models. Mice fed a low-iron diet prior to implanting tumor cells showed significantly delayed tumor growth. In addition, staining iron deposits, it became apparent that tumors outcompete the natural iron reservoirs in liver and spleen. As a result, RBC recycling and iron storage in liver and spleen are compromised and erythropoiesis is significantly reduced, finally provoking anemia. A recent study from Theurl and colleagues provides a sophisticated study of RBC clearance and iron recycling in a mouse model. Senescent RBCs are taken up by monocytes in the bloodstream and transported to both liver and spleen. Interestingly, accumulation of iron-recycling macrophages was exclusively observed in the liver, thus identifying the liver as the main organ for RBC recycling. These findings are of crucial importance since the recycling of senescent RBC by reticuloendothelial macrophages is of utmost importance to recover iron in order to ensure efficient erythropoiesis.

A growing number of studies explore the role of iron-related proteins in the context of cancer. Apparently, the expression of different iron-regulated genes such as the transferrin receptor (TfR1), ferritin light chain (FTL), and the iron regulatory protein (IRP)-2 in tumor cells correlated with a poor prognosis, a higher tumor grade, and increased chemoresistance. Given the complex network of iron regulatory genes in cancer cells and their role for tumor growth and survival, a better understanding of their regulation and interplay is warranted. The identification of recently acknowledged new iron-regulated genes, such as lipocalin-2 (Lcn-2) as well as siderophore-binding proteins, might help to understand how the tumor exploits systemic and local iron management.

2. Iron Metabolism in Cancer Cells

Circulating iron is normally found complexed in transferrin (Tf), circulating in the bloodstream. Tf is taken up in peripheral tissue by binding to the TfR1. The ligand–receptor complex is endocytosed and recycled within the endosome, releasing ferric iron, which is exported into the cytosol by the divalent metal transporter (DMT)-1. High TfR1 expression correlated not only with a reduced response to chemotherapy, but also increased phosphorylation of src in breast cancer, promoting tumor cell division, motility, and adhesion. Moreover, the homologous TfR2 is also frequently upregulated in cancer cells. Therefore, the Tf/TfR system not only enhances iron uptake, but also provokes tumor cell survival. Ultimately, tumor cells adjust intracellular iron metabolism to favor iron accumulation, by increasing iron uptake and storage, at the same time decreasing iron export. Imported iron enters the bioactive labile iron pool (LIP), which provides it for metabolic and proliferative purposes. The amount of the LIP is sensed by post-transcriptional mechanisms of cytosolic iron-regulated RNA binding proteins 1 and 2 (IRP-1 and IRP-2) to fine-tune uptake, storage, and release of iron. When intracellular iron is low, IRPs interact with conserved iron-responsive elements (IREs) in the untranslated regions (UTRs) of central genes accounting for iron homeostasis. Binding of IRPs to IREs in the 5’-UTR attenuates translation, whereas binding to IREs in the 3’-UTR stabilizes respective mRNAs and fosters translation. Thus, when iron is high, mRNAs of TfR and DMT-1 are unstable and get degraded, which ultimately decreases iron uptake and transport. Simultaneously, iron storage is enhanced by releasing the translational blockade of ferritin (FT) heavy chain (FTH) and FTL. Thereby, excess iron that is not utilized, can be stored in the iron storage protein FT and can later be accessed by ferritinophagy. Breast cancer cells with a more aggressive mesenchymal phenotype display higher amounts of intracellular FT. Moreover, serum concentrations of FT are increased in cancer patients compared to healthy individuals. For this reason, the expression of FT is considered a prognostic marker for some cancer subtypes such as squamous cell carcinoma or breast cancer. Interestingly, extracellular FT stimulates proliferation of breast cancer cells independently of the iron content, acting as an inflammatory effector mechanism to directly support tumorigenesis.

Iron, when neither metabolically used nor stored in FT, is exported from cells to the circulation by the iron exporter ferroportin (FPN), gets oxidized by ceruloplasmin or hephaestin, and is loaded to Tf. The FPN efflux system represents one of the key mechanisms to adjust the iron amount in the body and to affect the ratio of stored and released iron. In invasive tumor areas, iron export via FPN is lower compared to normal tissue, with the notion that FPN expression in carcinomas inversely correlated with patient survival and disease outcome. A decreased FPN expression in tumor cells is associated with enhanced availability of LIP-associated iron in cultured breast cancer cells. This effect increased tumor growth in a breast cancer xenograft model, correlating with the aggressiveness of breast cancer subtypes. Consistently, an increased expression of FPN in tumor cells correlated with better patient outcome, as does the absence of estrogen receptor, low histological grade, or a low grade of lymph metastasis. The expression of FPN is regulated by the acute-phase protein hepcidin, which induces internalization and degradation of FPN upon its binding, thereby attenuating the iron export capacity. Peripheral tissues also secrete hepcidin, which, unlike liver-secreted hepcidin, is thought to act locally. Tissue sequestration and systemic iron levels are regulated by hepcidin, by controlling FPN-facilitated iron release into the plasma of all cells that handle iron, including intestinal enterocytes, hepatocytes, and macrophages. Levels of hepcidin are increased during inflammation and decreased by iron insufficiency and erythropoiesis. In cancer patients, hepcidin levels are often elevated, likely because of cancer driven inflammation. Enhanced hepcidin expression in breast cancer patients points to an autocrine/paracrine regulatory mechanism in order to reduce control local tumor iron efflux. A scheme describing how tumors exploit physiological iron resources is given in Figure 1.

3. Iron in the Tumor Microenvironment—Role of Tumor-Associated Macrophages

The role of iron for cancer development is tightly linked to its ability to modulate innate and adaptive immune responses of macrophages or T cells. In order to control iron availability, immune cells adapt their phenotype accordingly to defend the host against invading pathogens. Since tumor cells might be recognized as foreign in the first place, it is not surprising that immune cells get polarized to adjust the iron metabolism at the systemic as well as local tumor levels. As a consequence, tumor cells compete for iron with immune cells of their local microenvironment. The inflammatory nature of the tumor microenvironment and the presence of inflammatory stimuli are critical regulators of iron availability. During early stages of carcinogenesis, pro-inflammatory cytokines endorse iron sequestration in macrophages and enhance the production of reactive oxygen species as a first-line anti-tumor defense. However, chronic inflammation or smoldering inflammation often creates an equilibrium between killing of immunogenic tumor cells and immune tolerance, finally driving tumor outgrowth. Outgrowth is supported as tumor cells often evade immune recognition or even acquire an immunosuppressive phenotype. Based on the intimate interplay of tumor cells and tumor-infiltrating immune cells, the latter ones are educated to a tumor-supportive, anti-inflammatory phenotype that significantly promotes tumor neovascularization, metastasis, growth and survival. In contrast to the iron sequestration phenotype of inflammatory macrophages induced by pro-inflammatory cytokines and danger-associated molecular patterns (DAMPs), anti-inflammatory macrophages and lymphocytes show an iron release phenotype, donating and distributing iron within the tumor microenvironment. These observations were recently underlined by Marques et al., describing an “iron utilization” phenotype of tumor cells, whereas tumor-infiltrating macrophages and lymphocytes represented an “iron donor” phenotype. In addition, macrophages are capable of ferritin secretion, whereby tumor growth is promoted. These findings were corroborated by a variety of studies showing ferritin expression mainly in the stromal compartment of tumor tissue. Of note, the appearance of tumor-supporting, iron-donating immune cells, in particular macrophages, is associated with tumor size and aggressiveness as well as poor patient prognosis.

Since macrophages are characterized by high functional plasticity and heterogeneity of activation, it is speculated that distinct macrophage subpopulations are found within the same tumor, with the individual phenotypes coined by their localization and microenvironmental stimuli. Therefore, it seems appropriate to consider polarization of the TAM as a continuum of functional activation phenotypes rather than distinct subpopulations. Consequently, some macrophage polarization states might support, whereas others antagonize tumor cells. These observations also hold true for the iron-regulated gene signature of distinct macrophage phenotypes. The profile can be characterized by expression of a particular subset of iron-regulated genes to take up iron, store it, or export it in order to donate it to neighboring cells. Pro-inflammatory macrophages are prone to iron retention. They display an iron sequestering phenotype characterized by enhanced iron uptake and storage, but attenuated release. In contrast, anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced. As alternatively activated macrophages scavenge senescent and/or apoptotic cells, they play an important role in tissue repair, regeneration, resolution of inflammation, and iron recycling. Consequently, they show a high expression of scavenger receptors such as CD163 and CD91. This allows for the uptake of iron-containing heme clusters, which in turn enhances the expression of heme oxygenase 1 (HO-1). The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated. The majority of the heme-recycled iron joins the LIP, with only a small proportion actually being stored in FT. Non-heme-bound iron can be taken up through the DMT-1. These features allow anti-inflammatory macrophages to rapidly mobilize and redistribute iron to the local microenvironment in order to support the demand of surrounding cells. This iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo.

Recently, we provided evidence that TAM adopt an iron-release phenotype due to their interaction with dying tumor cells, whereby iron availability was increased within the tumor microenvironment. Under these conditions, TAM expressed higher levels of the high-affinity iron-binding protein lipocalin-2 (Lcn-2). Lcn-2 turned out to export iron from TAM, while depletion of the established iron exporter FPN did not alter their iron release capacity. These observations suggest the existence of an alternative iron transport pathway in the tumor microenvironment, operating independently of FPN. The inability of FPN to add to iron export under these conditions might be the local expression of hepcidin, which compromises its expression. Interestingly, large amounts of hepcidin are found both within the tumor microenvironment and systemically in cancer patients. However, recent findings suggest that excess amounts of heme or iron in hemorrhagic tumor areas are detrimental to the macrophage iron phenotype by shifting the anti-inflammatory, pro-tumor macrophage phenotype to a pro-inflammatory and thus anti-tumoral one. These observations are somehow mirrored when macrophages are exposed to hemolytic RBCs during e.g., sickle cell anemia. Based on the heme-induced polarization shift, macrophages acquire a more pro-inflammatory phenotype and exacerbate tissue damage. Additional studies support the idea that excess iron predispose macrophages towards a pro-inflammatory phenotype, thereby linking macrophage iron handling to their role in inflammatory disease.

Since tumors demand an excess of iron, both during early steps of tumor development and late metastatic processes, recent paradigms of macrophage iron polarization are of clinical interest. The fact that TAMs actively release iron to the tumor microenvironment positions them at the center of pathways associated with the concepts established as the “hallmarks of cancer”. Further investigations and mechanistic insights regarding the development of TAM heterogeneity and functional iron plasticity are urgently needed.

4. Strategies to Target Iron Trafficking in the Tumor Microenvironment

Iron handling in the tumor microenvironment emerged as an important aspect of tumorigenesis. Since hepcidin arises as a key iron-regulated gene due to its function as a sensor for systemic iron availability, several strategies are envisioned to manipulate its expression. First, pharmacological approaches used neutralizing antibodies or aptamers to directly target hepcidin. Other ways to control hepcidin expression are based on inhibition of bone morphogenic proteins (BMPs)/SMAD as well as IL-6/signal transducers and activators of transcription (STAT) 3 signaling pathways. Interfering with IL-6 signaling using tocilizumab, an antibody directed against the IL-6 receptor was effective in treating chronic anemia associated with arthritis. First promising anti-cancer efficacy was recently provided by the simultaneous inhibition of the IL-6 receptor using tocilizumab and the IL-8 receptor by reparixin, showing significantly decreased metastasis of breast cancer cells to the lung, liver, and lymph nodes in a mouse mammary xenograft model. However, no direct correlation of synergistically blocking the IL-6 and IL-8 receptors and hepcidin expression or the effect on cancer-related anemia was reported in this study. However, it seems that blocking hepcidin through manipulation of the IL-6 signaling cascade is feasible for the treatment of cancer anemia.

Current approaches aim at reactivating iron release from the reticuloendothelial system, which is compromised during tumor development and manifested as anemia in cancer patients. As prospective clinical data are still missing, the approach to targeting hepcidin for cancer treatment is still not fully accepted. The same holds true for directly neutralizing hepcidin using antibodies. Many of the currently available drugs and/or antibodies interfering with hepcidin expression or activation show promising effects in the treatment of chronic anemia, which is also found in cancer patients. Due to a lack of long-term follow-up studies in cancer patients, it is difficult to predict both the efficacy and safety of those drugs in cancer treatment. There are also attempts to develop FPN stabilizers in order to reactivate iron efflux form tumor cells. As pathways regulating the hepcidin-FPN axis are complex, the majority of present pharmacological strategies aim at acutely interfering with protein expression and/or activity. Cancer cells reprogram their iron metabolism to increase net iron influx. This is accomplished by upregulating proteins for iron uptake such as Tf. The Tf/TfR system represents one of the major routes for iron acquisition, both in normal and malignant cells. Upregulation of this highly conserved iron acquisition pathway is found in a variety of cancers, including breast and colon. Thus, it appears logic to apply an anti-TfR strategy as a therapeutic measure. Roughly 30 years ago, initial studies were conducted to explore the anti-neoplastic capacity of anti-TfR monoclonal antibodies. Phase I trials provided promising results, without any indication of major side effects in patients. However, treatment was only effective in some cancers such as adult T-cell leukemia/lymphoma (ATL) and leukemia. Further studies revealed that anti-TfR treatment was specifically encouraging for therapeutic approaches in hematologic cancer due to the fact that cells of the hematopoietic lineage are highly iron-dependent. At the same time, these observations raised major concerns for the use of anti-TfR antibodies for the treatment of other tumor types. The problem may arise that maturing erythroid cells would severely be affected by anti-TfR antibodies, which, in turn, may disturb erythropoiesis and cause anemia. Taking the upregulation of the TfR on the tumor cell surface into account, a Trojan horse strategy was tested to shuttle therapeutic molecules into malignant cells. In fact, a variety of studies confirmed an improved anti-cancer drug uptake upon conjugation to a TfR monoclonal antibody. Not only to mention that TfR expression is significantly upregulated on cancer cells, it also represents a very effective receptor-mediated endocytosis system. Therefore, the Tf–TfR system is considered a promising target to enhance the uptake of drugs that are specifically conjugated to Tf to be recognized by the TfR and to facilitate uptake in, i.e. multidrug-resistant tumor cells. The exceptional capacity to transport drugs across the blood–brain barrier makes the Tf–TfR axis valuable for the treatment of brain tumors through TfR-mediated transcytosis. As the TfR is expressed at high levels at the blood–brain barrier due to its physiological function to deliver iron to the brain, it is one of the most studied molecules for receptor-mediated drug delivery to the brain. Using either Tf or TfR as targeting moieties, current studies with both direct conjugation and immunotoxins focus mainly on the development of treatment approaches against brain tumors. Another consideration is the uptake of secreted FT by the TfR. Since FT assembles into spherical cage-like structures and has the potential to reversibly disassemble within cells, it represents an attractive target for nanostructure research in the cancer context. Such naturally occurring structures are advantageous over synthetically ones due to their low toxicity and negligible immune responses. FT nanocages are used to encapsulate chemotherapeutic agents such as doxorubicin or gold ions to induce tumor cell death.

It needs also consideration that cancer cells might have evolved alternative strategies to take up iron trough hitherto-unappreciated transport proteins. Lcn-2 might accomplish such a role due to its ability to scavenge iron-loaded siderophores. Siderophores are small, low-molecular-mass iron-binding ligands known from iron acquisition mechanisms used by bacteria. Interestingly, also higher organisms such as fungi or mammals are able of producing this type of iron-scavenging molecules. Lcn-2 shows an extraordinary high affinity to bind iron-loaded catecholate-type siderophores. However, it still remains unclear if siderophores are indeed produced in mammals to mediate Lcn-2–iron binding or if Lcn-2 takes advantage of bacterial siderophores, residing within mammals from e.g., commensal bacteria. A recent study proposes that bacterial siderophores do not only serve as iron scavengers to limit bacterial growth, but are also able to support the host’s iron homeostasis. Binding to the α subunit of ATP synthase, mitochondrial iron uptake is promoted by enterobactin, secreted from commensal bacteria. These features have to be considered with regard to the iron-transporting function of Lcn-2, taking its extraordinary function in innate immunity into account. Another aspect of Lcn-2 during infectious diseases is its ability to control neutrophil function. Neutrophils from Lcn-2–/– animals do not migrate to sites of infection and do no longer respond to chemotactic stimuli, which however can be reverted by the addition of recombinant Lcn-2.

Lcn-2 is recognized and internalized by cells via their highly expressed high-affinity Lcn-2 receptor (Lcn-2R) and/or the low-affinity megalin receptor. Several studies in humans suggest Lcn-2 as a pro-tumorigenic factor in breast cancer, correlating with a decreased survival and reduced responsiveness to neoadjuvant chemotherapy. It has been observed that human breast tumors contain enhanced amounts of Lcn-2, especially during advanced stages. Consistently, elevated Lcn-2 levels in the urine of breast cancer patients are correlated with a poor metastatic outcome. Additionally, experimental transgenic tumor-bearing mouse mammary tumor virus (PyMT) mice exhibit higher Lcn-2 plasma levels compared to controls, and Lcn-2-deficient PyMT mice developed fewer tumors than Lcn-2-competent littermates. Corroborating the role of Lcn-2, expression of Lcn-2R is also indicative for a poor prognosis, and a reduced survival rate but increased invasion in several cancer entities. These observations strengthen the concept that Lcn-2 promotes its pro-tumor functions via Lcn-2R signaling. Lcn-2 was also shown to induce epithelial-to-mesenchymal transition (EMT) through upregulation of the EMT-associated transcription factors Snail1, Slug, and Twist1, which, in turn, influence the expression of epithelial and mesenchymal markers to promote invasiveness. While the majority of studies so far focused on mechanisms promoted by tumor cell-derived Lcn-2, recent data from our group suggest that stromal Lcn-2 promoted metastasis by enhancing EMT and lymphangiogenesis. Moreover, we proposed that iron might be the missing link to understand the tumor-promoting role of Lcn-2. In fact, it was speculated that the iron load of Lcn-2 defines pro-tumor characteristics of Lcn-2. However, it is still unknown how tumor cells selectively take up iron-loaded Lcn-2 relative to iron-free Lcn-2 or how the latter is antagonized within tumor cells in order to avoid its reported apoptotic effects.

5. Novel Iron Chelation-Based Treatment Strategies

Cancer cells have a higher demand for iron in order to sustain their proliferative capacity. Considering this as their Achilles’ heel, several approaches seek to interfere with iron handling in cancer cells, either by directly modulating iron-regulated genes or by using iron chelators. The anti-neoplastic potential of iron chelators is accomplished, at least in part, by inhibiting DNA synthesis, causing a G1-S-phase cell cycle arrest, attenuating EMT, correcting epigenetic signatures of malignant tumor cells, and/or promoting cancer cell apoptosis. For instance, the natural siderophore desferrioxamine (DFO, Desferal®) as well as the synthetic chelator derasirox (DFX, Exiade), which are clinically employed to treat iron overload due to chronic blood transfusion therapy, and the thiosemicarbazone Triapine® have shown promising anti-cancer activity in clinical trials. Unfortunately, due to serious side effects in several cases, e.g., hearing abnormalities, nephropathy, optic neuropathy, and growth failure in children, their applicability during cancer treatment is hampered. While most studies aim at targeting iron in tumor cells, approaches to addressing iron chelation in cells of the tumor microenvironment is still lacking. Generally, employing metal chelators in the context of cancer treatment remains challenging, when compared to their applications for systemic iron depletion. Fundamental to successfully approach chelation therapy in cancer will be the capacity to target iron selectively in malignant cells without affecting normal tissue or the extracellular space. Chelators derived from bacterial siderophores (e.g., DFO) or other high-affinity scaffolds (e.g., Triapine) lack the required selectivity and thus are not designed to target specifically the higher iron demand of malignant cancer cells, which generally show normal or low systemic iron levels. Moreover, the high hydrophilicity and unfavorable pharmacokinetics of several chelators do not allow reaching effective intratumoral concentrations. To date, none of the iron chelators employed in the clinic for iron overload disorders has obtained approval for the cancer setting. More recently, high-throughput screening identified an iron chelating agent as a promising drug candidate for colon cancer (VLX600), which entered a Phase I clinical trial (identifier: NCT02222363) for refractory advanced solid tumors. A summary of pre-clinical studies and clinical trials that target tumor iron metabolism is given in Table 1.

Prodrug strategies are currently under investigation in order to implement specific prodrug activation/action. The use of disulfide bonds as the activation switch of iron prochelators showed encouraging results in vitro, as iron coordination only occurs following intracellular disulfide reduction, leading to the formation of high-affinity tridentate thiolate chelators. It can be envisioned that a higher reducing environment in cancer cells, compared to the surrounding tissue, makes reductive activation an attractive strategy to enhance cancer cell specificity, owing to higher amounts of reduced glutathione compared to healthy, neighboring cells. Because of the stability of disulfide linkages in blood plasma, an advantage of the prochelator strategy is their potential supplementation at high doses, which may foster their uptake by tumor cells, while avoiding unwanted side effects in plasma. Disulfide linkers can also be employed to attach tumor-targeting units aimed at imparting higher cancer selectivity. Supported by the widespread clinical use of radiolabeled glucose analogs for tumor visualization by positron emission tomography (PET), glycoconjugation is undergoing intense scrutiny as a method to increase specificity of anti-proliferative agents. Akam et al. explored glucose-conjugated thiosemicarbazone prochelators in colon carcinoma, proving enhanced prochelator accumulation in malignant cells. These approaches exploit overexpression of the glucose transporter GLUT1 in a large fraction of cancer phenotypes. Glucose conjugates of several cancer chemotherapeutics, including paclitaxel and doxorubicin, experienced a higher therapeutic efficacy in vivo. These strategies may also be exerted to achieve selectivity in targeting the iron pool of tumor cells.

While most of the current chelator-based intervention strategies focus on tumor cells, targeting iron in the tumor microenvironment has not been explored significantly. Considering that macrophages constitute a major infiltrate in solid tumors and taking their pivotal role in iron metabolism into account, these immune cells are likely a worthwhile target in anti-cancer strategies. We employed the disulfide-based prochelator (TC3-S)2 to explore how iron sequestration in macrophages affects their iron homeostasis. Upon intracellular reduction, (TC3-S)2 is converted to the thiol chelator TC3-SH, which re-programmed macrophages from an iron release to and iron sequestration phenotype. Future in vivo studies using this approach should address the potentially impactful possibility to interfere with tumor progression by using macrophage-targeted chelation strategies.

Another recent possibility to target excess iron in tumor cells is through induction of ferroptosis, an iron-dependent and peroxidation-driven form of cell death. This type of cell death was recently shown to be executed via the tumor suppressor p53, suggesting a natural anti-tumor role of ferroptosis. Interestingly, especially therapy-resistant and drug-tolerant tumor cells are prone to ferroptosis. Thus, it might be speculated that inducers of ferroptosis emerge as novel and rather selective anti-cancer drugs.

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    Jian J., Yang Q., Shao Y., Axelrod D., Smith J., Singh B., Krauter S., Chiriboga L., Yang Z., Li J., et al. A link between premenopausal iron deficiency and breast cancer malignancy. BMC Cancer. 2013;13:307.

    Not in our library10.1186/1471-2407-13-307

  23. 23.

    Freitas I., Boncompagni E., Vaccarone R., Fenoglio C., Barni S., Baronzio G.F. Iron accumulation in mammary tumor suggests a tug of war between tumor and host for the microelement. Anticancer Res. 2007;27:3059-3065.

    Not in our library

  24. 24.

    Theurl I., Hilgendorf I., Nairz M., Tymoszuk P., Haschka D., Asshoff M., He S., Gerhardt L.M., Holderried T.A., Seifert M., et al. On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat. Med. 2016;22:945-951.

    Not in our library10.1038/nm.4146

  25. 25.

    Green C.J., Attwood K., Sharma N.J., Gross K.W., Smith G.J., Xu B., Kauffmann E.C. Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients. Oncotarget. 2017;8:107052-107075.

    Not in our library10.18632/oncotarget.22323

  26. 26.

    Rossiello R., Carriero M.V., Giordano G.G. Distribution of ferritin, transferrin and lactoferrin in breast carcinoma tissue. J. Clin. Pathol. 1984;37:51-55.

    Not in our library10.1136/jcp.37.1.51

  27. 27.

    Jezequel P., Campion L., Spyratos F., Loussouarn D., Campone M., Guerin-Charbonnel C., Joalland M.P., Andre J., Descotes F., Grenot C., et al. Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: A multicentric 2004 national PHRC study. Int. J. Cancer. 2012;131:426-437.

    Not in our library10.1002/ijc.26397

  28. 28.

    Wang W., Deng Z., Hatcher H., Miller L.D., Di X., Tesfay L., Sui G., D’Agostino R.B., Torti F.M., Torti S.V. IRP2 regulates breast tumor growth. Cancer Res. 2014;74:497-507.

    Not in our library10.1158/0008-5472.can-13-1224

  29. 29.

    Calzolari A., Deaglio S., Maldi E., Cassoni P., Malavasi F., Testa U. TfR2 expression in human colon carcinomas. Blood Cells Mol. Dis. 2009;43:243-249.

    Not in our library10.1016/j.bcmd.2009.08.001

  30. 30.

    Calzolari A., Finisguerra V., Oliviero I., Deaglio S., Mariani G., Malavasi F., Testa U. Regulation of transferrin receptor 2 in human cancer cell lines. Blood Cells Mol. Dis. 2009;42:5-13.

    Not in our library10.1016/j.bcmd.2008.10.001

  31. 31.

    Jian J., Yang Q., Huang X. Src regulates Tyr(20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival. J. Biol. Chem. 2011;286:35708-35715.

    Not in our library10.1074/jbc.m111.271585

  32. 32.

    Hentze M.W., Muckenthaler M.U., Galy B., Camaschella C. Two to tango: Regulation of Mammalian iron metabolism. Cell. 2010;142:24-38.

    Not in our library10.1016/j.cell.2010.06.028

  33. 33.

    Muckenthaler M.U., Galy B., Hentze M.W. Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu. Rev. Nutr. 2008;28:197-213.

    Not in our library10.1146/annurev.nutr.28.061807.155521

  34. 34.

    Donfrancesco A., Deb G., Dominici C., Pileggi D., Castello M.A., Helson L. Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res. 1990;50:4929-4930.

    Not in our library

  35. 35.

    Orlandi R., De Bortoli M., Ciniselli C.M., Vaghi E., Caccia D., Garrisi V., Pizzamiglio S., Veneroni S., Bonini C., Agresti R., et al. Hepcidin and ferritin blood level as noninvasive tools for predicting breast cancer. Ann. Oncol. 2014;25:352-357.

    Not in our library10.1093/annonc/mdt490

  36. 36.

    Weinstein R.E., Bond B.H., Silberberg B.K. Tissue ferritin concentration in carcinoma of the breast. Cancer. 1982;50:2406-2409.

    Not in our library10.1002/1097-0142(19821201)50:11<2406::aid-cncr2820501127>3.0.co;2-s

  37. 37.

    Weinstein R.E., Bond B.H., Silberberg B.K., Vaughn C.B., Subbaiah P., Pieper D.R. Tissue ferritin concentration and prognosis in carcinoma of the breast. Breast Cancer Res. Treat. 1989;14:349-353.

    Not in our library10.1007/bf01806307

  38. 38.

    Mallon E., Osin P., Nasiri N., Blain I., Howard B., Gusterson B. The basic pathology of human breast cancer. J. Mammary Gland Biol. Neoplasia. 2000;5:139-163.

    Not in our library10.1023/a:1026439204849

  39. 39.

    Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-444.

    Not in our library10.1038/nature07205

  40. 40.

    Alkhateeb A.A., Han B., Connor J.R. Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res. Treat. 2013;137:733-744.

    Not in our library10.1007/s10549-012-2405-x

  41. 41.

    Donovan A., Lima C.A., Pinkus J.L., Pinkus G.S., Zon L.I., Robine S., Andrews N.C. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191-200.

    Not in our library10.1016/j.cmet.2005.01.003

  42. 42.

    Pinnix Z.K., Miller L.D., Wang W., D’Agostino R., Kute T., Willingham M.C., Hatcher H., Tesfay L., Sui G., Di X., et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci. Transl. Med. 2010;2:43ra56.

    Not in our library10.1126/scitranslmed.3001127

  43. 43.

    De Domenico I., Ward D.M., Langelier C., Vaughn M.B., Nemeth E., Sundquist W.I., Ganz T., Musci G., Kaplan J. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol. Biol. Cell. 2007;18:2569-2578.

    Not in our library10.1091/mbc.e07-01-0060

  44. 44.

    Nemeth E., Tuttle M.S., Powelson J., Vaughn M.B., Donovan A., Ward D.M., Ganz T., Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.

    Not in our library10.1126/science.1104742

  45. 45.

    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783-788.

    Not in our library10.1182/blood-2003-03-0672

  46. 46.

    Nemeth E., Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122:78-86.

    Not in our library10.1159/000243791

  47. 47.

    Darshan D., Anderson G.J. Interacting signals in the control of hepcidin expression. Biometals. 2009;22:77-87.

    Not in our library10.1007/s10534-008-9187-y

  48. 48.

    Sasu B.J., Li H., Rose M.J., Arvedson T.L., Doellgast G., Molineux G. Serum hepcidin but not prohepcidin may be an effective marker for anemia of inflammation (AI). Blood Cells Mol. Dis. 2010;45:238-245.

    Not in our library10.1016/j.bcmd.2010.07.013

  49. 49.

    Butterfield A.M., Luan P., Witcher D.R., Manetta J., Murphy A.T., Wroblewski V.J., Konrad R.J. A dual-monoclonal sandwich ELISA specific for hepcidin-25. Clin. Chem. 2010;56:1725-1732.

    Not in our library10.1373/clinchem.2010.151522

  50. 50.

    Marques O., Porto G., Rema A., Faria F., Cruz Paula A., Gomez-Lazaro M., Silva P., Martins da Silva B., Lopes C. Local iron homeostasis in the breast ductal carcinoma microenvironment. BMC Cancer. 2016;16:187.

    Not in our library10.1186/s12885-016-2228-y

  51. 51.
    Iron at the interface of immunity and infection · 2014
    No notice
  52. 52.

    Schaible U.E., Kaufmann S.H. Iron and microbial infection. Nat. Rev. Microbiol. 2004;2:946-953.

    Not in our library10.1038/nrmicro1046

  53. 53.

    Thevenod F. Iron and Its Role in Cancer Defense: A Double-Edged Sword. Met. Ions Life Sci. 2018;18.

    Not in our library10.1515/9783110470734-021

  54. 54.

    Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-1570.

    Not in our library10.1126/science.1203486

  55. 55.

    Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer. 2005;5:263-274.

    Not in our library10.1038/nrc1586

  56. 56.

    Tang X. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett. 2013;332:3-10.

    Not in our library10.1016/j.canlet.2013.01.024

  57. 57.

    Yu J.L., Rak J.W. Host microenvironment in breast cancer development: Inflammatory and immune cells in tumour angiogenesis and arteriogenesis. Breast Cancer Res. 2003;5:83-88.

    Not in our library10.1186/bcr573

  58. 58.
    Mechanisms Driving Macrophage Diversity and Specialization in Distinct Tumor Microenvironments and Parallelisms with Other Tissues · 2014
    No notice
  59. 59.

    Biswas S.K., Allavena P., Mantovani A. Tumor-associated macrophages: Functional diversity, clinical significance, and open questions. Semin. Immunopathol. 2013;35:585-600.

    Not in our library10.1007/s00281-013-0367-7

  60. 60.

    Casazza A., Laoui D., Wenes M., Rizzolio S., Bassani N., Mambretti M., Deschoemaeker S., Van Ginderachter J.A., Tamagnone L., Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013;24:695-709.

    Not in our library10.1016/j.ccr.2013.11.007

  61. 61.

    Movahedi K., Laoui D., Gysemans C., Baeten M., Stange G., Van den Bossche J., Mack M., Pipeleers D., In’t Veld P., De Baetselier P., et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70:5728-5739.

    Not in our library10.1158/0008-5472.can-09-4672

  62. 62.

    Torroella-Kouri M., Silvera R., Rodriguez D., Caso R., Shatry A., Opiela S., Ilkovitch D., Schwendener R.A., Iragavarapu-Charyulu V., Cardentey Y., et al. Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. Cancer Res. 2009;69:4800-4809.

    Not in our library10.1158/0008-5472.can-08-3427

  63. 63.

    Umemura N., Saio M., Suwa T., Kitoh Y., Bai J., Nonaka K., Ouyang G.F., Okada M., Balazs M., Adany R., et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J. Leukoc. Biol. 2008;83:1136-1144.

    Not in our library10.1189/jlb.0907611

  64. 64.

    Cairo G., Recalcati S., Mantovani A., Locati M. Iron trafficking and metabolism in macrophages: Contribution to the polarized phenotype. Trends Immunol. 2011;32:241-247.

    Not in our library10.1016/j.it.2011.03.007

  65. 65.

    Lane D.J., Merlot A.M., Huang M.L., Bae D.H., Jansson P.J., Sahni S., Kalinowski D.S., Richardson D.R. Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease. Biochim. Biophys. Acta. 2015;1853:1130-1144.

    Not in our library10.1016/j.bbamcr.2015.01.021

  66. 66.

    Mertens C., Mora J., Oren B., Grein S., Winslow S., Scholich K., Weigert A., Malmstrom P., Forsare C., Ferno M., et al. Macrophage-derived lipocalin-2 transports iron in the tumor microenvironment. Oncoimmunology. 2018;7:e1408751.

    Not in our library10.1080/2162402x.2017.1408751

  67. 67.

    Recalcati S., Locati M., Marini A., Santambrogio P., Zaninotto F., De Pizzol M., Zammataro L., Girelli D., Cairo G. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur. J. Immunol. 2010;40:824-835.

    Not in our library10.1002/eji.200939889

  68. 68.

    Gregory C.D., Devitt A. The macrophage and the apoptotic cell: An innate immune interaction viewed simplistically? Immunology. 2004;113:1-14.

    Not in our library10.1111/j.1365-2567.2004.01959.x

  69. 69.

    Soe-Lin S., Apte S.S., Mikhael M.R., Kayembe L.K., Nie G., Ponka P. Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. Exp. Hematol. 2010;38:609-617.

    Not in our library10.1016/j.exphem.2010.04.003

  70. 70.

    Leftin A., Ben-Chetrit N., Klemm F., Joyce J.A., Koutcher J.A. Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer. PLoS ONE. 2017;12:e0184765.

    Not in our library10.1371/journal.pone.0184765

  71. 71.

    Leftin A., Zhao H., Turkekul M., de Stanchina E., Manova K., Koutcher J.A. Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. Sci. Rep. 2017;7:11632.

    Not in our library10.1038/s41598-017-11899-2

  72. 72.

    Mertens C., Akam E.A., Rehwald C., Brune B., Tomat E., Jung M. Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PLoS ONE. 2016;11:e0166164.

    Not in our library10.1371/journal.pone.0166164

  73. 73.

    Tesfay L., Clausen K.A., Kim J.W., Hegde P., Wang X., Miller L.D., Deng Z., Blanchette N., Arvedson T., Miranti C.K., et al. Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res. 2015;75:2254-2263.

    Not in our library10.1158/0008-5472.can-14-2465

  74. 74.

    Miller L.D., Coffman L.G., Chou J.W., Black M.A., Bergh J., D’Agostino R., Torti S.V., Torti F.M. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 2011;71:6728-6737.

    Not in our library10.1158/0008-5472.can-11-1870

  75. 75.

    Vela D., Vela-Gaxha Z. Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications. Exp. Mol. Med. 2018;50:e436.

    Not in our library10.1038/emm.2017.273

  76. 76.

    Zhang S., Chen Y., Guo W., Yuan L., Zhang D., Xu Y., Nemeth E., Ganz T., Liu S. Disordered hepcidin-ferroportin signaling promotes breast cancer growth. Cell Signal. 2014;26:2539-2550.

    Not in our library10.1016/j.cellsig.2014.07.029

  77. 77.
    Iron Induces Anti-tumor Activity in Tumor-Associated Macrophages · 2017
    No notice
  78. 78.

    Vinchi F., Costa da Silva M., Ingoglia G., Petrillo S., Brinkman N., Zuercher A., Cerwenka A., Tolosano E., Muckenthaler M.U. Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease. Blood. 2016;127:473-486.

    Not in our library10.1182/blood-2015-08-663245

  79. 79.

    Kroner A., Greenhalgh A.D., Zarruk J.G., Passos Dos Santos R., Gaestel M., David S. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron. 2014;83:1098-1116.

    Not in our library10.1016/j.neuron.2014.07.027

  80. 80.

    Sindrilaru A., Peters T., Wieschalka S., Baican C., Baican A., Peter H., Hainzl A., Schatz S., Qi Y., Schlecht A., et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Investig. 2011;121:985-997.

    Not in our library10.1172/jci44490

  81. 81.

    Gardenghi S., Ramos P., Marongiu M.F., Melchiori L., Breda L., Guy E., Muirhead K., Rao N., Roy C.N., Andrews N.C., et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J. Clin. Investig. 2010;120:4466-4477.

    Not in our library10.1172/jci41717

  82. 82.
    Hepcidin: regulation of the master iron regulator · 2015
    No notice
  83. 83.

    Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu. Rev. Nutr. 2010;30:105-122.

    Not in our library10.1146/annurev.nutr.012809.104804

  84. 84.

    Song S.N., Tomosugi N., Kawabata H., Ishikawa T., Nishikawa T., Yoshizaki K. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116:3627-3634.

    Not in our library10.1182/blood-2010-03-271791

  85. 85.
    Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration · 2017
    No notice
  86. 86.

    Poli M., Asperti M., Ruzzenenti P., Regoni M., Arosio P. Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front. Pharmacol. 2014;5:86.

    Not in our library10.3389/fphar.2014.00086

  87. 87.

    Blanchette N.L., Manz D.H., Torti F.M., Torti S.V. Modulation of hepcidin to treat iron deregulation: Potential clinical applications. Expert Rev. Hematol. 2016;9:169-186.

    Not in our library10.1586/17474086.2016.1124757

  88. 88.

    Jung M., Mertens C., Bauer R., Rehwald C., Brune B. Lipocalin-2 and iron trafficking in the tumor microenvironment. Pharmacol. Res. 2017;120:146-156.

    Not in our library10.1016/j.phrs.2017.03.018

  89. 89.

    Tortorella S., Karagiannis T.C. Transferrin receptor-mediated endocytosis: A useful target for cancer therapy. J. Membr. Biol. 2014;247:291-307.

    Not in our library10.1007/s00232-014-9637-0

  90. 90.

    Faulk W.P., Hsi B.L., Stevens P.J. Transferrin and transferrin receptors in carcinoma of the breast. Lancet. 1980;2:390-392.

    Not in our library10.1016/s0140-6736(80)90440-7

  91. 91.

    Habashy H.O., Powe D.G., Staka C.M., Rakha E.A., Ball G., Green A.R., Aleskandarany M., Paish E.C., Douglas Macmillan R., Nicholson R.I., et al. Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen. Breast Cancer Res. Treat. 2010;119:283-293.

    Not in our library10.1007/s10549-009-0345-x

  92. 92.

    Brookes M.J., Hughes S., Turner F.E., Reynolds G., Sharma N., Ismail T., Berx G., McKie A.T., Hotchin N., Anderson G.J., et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut. 2006;55:1449-1460.

    Not in our library10.1136/gut.2006.094060

  93. 93.

    Radulescu S., Brookes M.J., Salgueiro P., Ridgway R.A., McGhee E., Anderson K., Ford S.J., Stones D.H., Iqbal T.H., Tselepis C., et al. Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Rep. 2012;2:270-282.

    Not in our library10.1016/j.celrep.2012.07.003

  94. 94.

    Mendelsohn J., Trowbridge I., Castagnola J. Inhibition of human lymphocyte proliferation by monoclonal antibody to transferrin receptor. Blood. 1983;62:821-826.

    Not in our library

  95. 95.

    Taetle R., Honeysett J.M., Trowbridge I. Effects of anti-transferrin receptor antibodies on growth of normal and malignant myeloid cells. Int. J. Cancer. 1983;32:343-349.

    Not in our library10.1002/ijc.2910320314

  96. 96.

    Trowbridge I.S., Lopez F. Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro. Proc. Natl. Acad. Sci. USA. 1982;79:1175-1179.

    Not in our library10.1073/pnas.79.4.1175

  97. 97.

    Brooks D., Taylor C., Dos Santos B., Linden H., Houghton A., Hecht T.T., Kornfeld S., Taetle R. Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6. Clin. Cancer Res. 1995;1:1259-1265.

    Not in our library

  98. 98.

    Taetle R., Castagnola J., Mendelsohn J. Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies. Cancer Res. 1986;46:1759-1763.

    Not in our library

  99. 99.

    Kozlowski R., Reilly I.A., Sowter D., Robins R.A., Russell N.H. Transferrin receptor expression of AML blasts is related to their proliferative potential. Br. J. Haematol. 1988;69:275-280.

    Not in our library10.1111/j.1365-2141.1988.tb07633.x

  100. 100.

    Moura I.C., Lepelletier Y., Arnulf B., England P., Baude C., Beaumont C., Bazarbachi A., Benhamou M., Monteiro R.C., Hermine O. A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood. 2004;103:1838-1845.

    Not in our library10.1182/blood-2003-07-2440

  101. 101.

    Daniels T.R., Bernabeu E., Rodriguez J.A., Patel S., Kozman M., Chiappetta D.A., Holler E., Ljubimova J.Y., Helguera G., Penichet M.L. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim. Biophys. Acta. 2012;1820:291-317.

    Not in our library10.1016/j.bbagen.2011.07.016

  102. 102.

    Xu L., Huang C.C., Huang W., Tang W.H., Rait A., Yin Y.Z., Cruz I., Xiang L.M., Pirollo K.F., Chang E.H. Systemic tumor-targeted gene delivery by anti-transferrin receptor scFv-immunoliposomes. Mol. Cancer Ther. 2002;1:337-346.

    Not in our library

  103. 103.

    Sahoo S.K., Labhasetwar V. Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention. Mol. Pharm. 2005;2:373-383.

    Not in our library10.1021/mp050032z

  104. 104.

    Paterson J., Webster C.I. Exploiting transferrin receptor for delivering drugs across the blood-brain barrier. Drug Discov. Today Technol. 2016;20:49-52.

    Not in our library10.1016/j.ddtec.2016.07.009

  105. 105.

    Dufes C., Al Robaian M., Somani S. Transferrin and the transferrin receptor for the targeted delivery of therapeutic agents to the brain and cancer cells. Ther. Deliv. 2013;4:629-640.

    Not in our library10.4155/tde.13.21

  106. 106.
    The Mouse Blood-Brain Barrier Transcriptome: A New Resource for Understanding the Development and Function of Brain Endothelial Cells · 2010
    No notice
  107. 107.

    Uchida Y., Ohtsuki S., Katsukura Y., Ikeda C., Suzuki T., Kamiie J., Terasaki T. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J. Neurochem. 2011;117:333-345.

    Not in our library10.1111/j.1471-4159.2011.07208.x

  108. 108.

    Bien-Ly N., Yu Y.J., Bumbaca D., Elstrott J., Boswell C.A., Zhang Y., Luk W., Lu Y., Dennis M.S., Weimer R.M., et al. Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J. Exp. Med. 2014;211:233-244.

    Not in our library10.1084/jem.20131660

  109. 109.

    Chen Q., Liu J. Transferrin and folic acid co-modified bufalin-loaded nanoliposomes: Preparation, characterization, and application in anticancer activity. Int. J. Nanomed. 2018;13:6009-6018.

    Not in our library10.2147/ijn.s176012

  110. 110.

    Gregori M., Orlando A., Re F., Sesana S., Nardo L., Salerno D., Mantegazza F., Salvati E., Zito A., Malavasi F., et al. Novel Antitransferrin Receptor Antibodies Improve the Blood-Brain Barrier Crossing Efficacy of Immunoliposomes. J. Pharm. Sci. 2016;105:276-283.

    Not in our library10.1016/j.xphs.2015.11.009

  111. 111.

    Niewoehner J., Bohrmann B., Collin L., Urich E., Sade H., Maier P., Rueger P., Stracke J.O., Lau W., Tissot A.C., et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron. 2014;81:49-60.

    Not in our library10.1016/j.neuron.2013.10.061

  112. 112.

    Ramalho M.J., Sevin E., Gosselet F., Lima J., Coelho M.A.N., Loureiro J.A., Pereira M.C. Receptor-mediated PLGA nanoparticles for glioblastoma multiforme treatment. Int. J. Pharm. 2018;545:84-92.

    Not in our library10.1016/j.ijpharm.2018.04.062

  113. 113.

    Li L., Fang C.J., Ryan J.C., Niemi E.C., Lebron J.A., Bjorkman P.J., Arase H., Torti F.M., Torti S.V., Nakamura M.C., et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl. Acad. Sci. USA. 2010;107:3505-3510.

    Not in our library10.1073/pnas.0913192107

  114. 114.

    Truffi M., Fiandra L., Sorrentino L., Monieri M., Corsi F., Mazzucchelli S. Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer. Pharmacol. Res. 2016;107:57-65.

    Not in our library10.1016/j.phrs.2016.03.002

  115. 115.

    Liang M., Fan K., Zhou M., Duan D., Zheng J., Yang D., Feng J., Yan X. H-ferritin-nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection. Proc. Natl. Acad. Sci. USA. 2014;111:14900-14905.

    Not in our library10.1073/pnas.1407808111

  116. 116.

    Monti D.M., Ferraro G., Petruk G., Maiore L., Pane F., Amoresano A., Cinellu M.A., Merlino A. Ferritin nanocages loaded with gold ions induce oxidative stress and apoptosis in MCF-7 human breast cancer cells. Dalton Trans. 2017;46:15354-15362.

    Not in our library10.1039/c7dt02370g

  117. 117.

    Behnsen J., Raffatellu M. Siderophores: More than Stealing Iron. MBio. 2016;7.

    Not in our library10.1128/mbio.01906-16

  118. 118.

    Smith K.D. Iron metabolism at the host pathogen interface: Lipocalin 2 and the pathogen-associated iroA gene cluster. Int. J. Biochem. Cell Biol. 2007;39:1776-1780.

    Not in our library10.1016/j.biocel.2007.07.003

  119. 119.

    Saha M., Sarkar S., Sarkar B., Sharma B.K., Bhattacharjee S., Tribedi P. Microbial siderophores and their potential applications: A review. Environ. Sci. Pollut. Res. Int. 2016;23:3984-3999.

    Not in our library10.1007/s11356-015-4294-0

  120. 120.

    Bao G., Clifton M., Hoette T.M., Mori K., Deng S.X., Qiu A., Viltard M., Williams D., Paragas N., Leete T., et al. Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat. Chem. Biol. 2010;6:602-609.

    Not in our library10.1038/nchembio.402

  121. 121.

    Devireddy L.R., Hart D.O., Goetz D.H., Green M.R. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 2010;141:1006-1017.

    Not in our library10.1016/j.cell.2010.04.040

  122. 122.
    Distinct Roles for Intra- and Extracellular Siderophores during Aspergillus fumigatus Infection · 2007
    No notice
  123. 123.

    Qi B., Han M. Microbial Siderophore Enterobactin Promotes Mitochondrial Iron Uptake and Development of the Host via Interaction with ATP Synthase. Cell. 2018;175:571-582.e11.

    Not in our library10.1016/j.cell.2018.07.032

  124. 124.

    Liu Z., Petersen R., Devireddy L. Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections. J. Immunol. 2013;190:4692-4706.

    Not in our library10.4049/jimmunol.1202411

  125. 125.

    Schroll A., Eller K., Feistritzer C., Nairz M., Sonnweber T., Moser P.A., Rosenkranz A.R., Theurl I., Weiss G. Lipocalin-2 ameliorates granulocyte functionality. Eur. J. Immunol. 2012;42:3346-3357.

    Not in our library10.1002/eji.201142351

  126. 126.

    Wenners A.S., Mehta K., Loibl S., Park H., Mueller B., Arnold N., Hamann S., Weimer J., Ataseven B., Darb-Esfahani S., et al. Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer. PLoS ONE. 2012;7:e45826.

    Not in our library10.1371/journal.pone.0045826

  127. 127.

    Yang J., McNeish B., Butterfield C., Moses M.A. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J. 2013;27:45-50.

    Not in our library10.1096/fj.12-211730

  128. 128.

    Bauer M., Eickhoff J.C., Gould M.N., Mundhenke C., Maass N., Friedl A. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res. Treat. 2008;108:389-397.

    Not in our library10.1007/s10549-007-9619-3

  129. 129.

    Yang J., Bielenberg D.R., Rodig S.J., Doiron R., Clifton M.C., Kung A.L., Strong R.K., Zurakowski D., Moses M.A. Lipocalin 2 promotes breast cancer progression. Proc. Natl. Acad. Sci. USA. 2009;106:3913-3918.

    Not in our library10.1073/pnas.0810617106

  130. 130.

    Berger T., Cheung C.C., Elia A.J., Mak T.W. Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc. Natl. Acad. Sci. USA. 2010;107:2995-3000.

    Not in our library10.1073/pnas.1000101107

  131. 131.

    Autelitano F., Loyaux D., Roudieres S., Deon C., Guette F., Fabre P., Ping Q., Wang S., Auvergne R., Badarinarayana V., et al. Identification of novel tumor-associated cell surface sialoglycoproteins in human glioblastoma tumors using quantitative proteomics. PLoS ONE. 2014;9:e110316.

    Not in our library10.1371/journal.pone.0110316

  132. 132.

    Miyamoto T., Asaka R., Suzuki A., Takatsu A., Kashima H., Shiozawa T. Immunohistochemical detection of a specific receptor for lipocalin2 (solute carrier family 22 member 17, SLC22A17) and its prognostic significance in endometrial carcinoma. Exp. Mol. Pathol. 2011;91:563-568.

    Not in our library10.1016/j.yexmp.2011.06.002

  133. 133.

    Jung M., Oren B., Mora J., Mertens C., Dziumbla S., Popp R., Weigert A., Grossmann N., Fleming I., Brune B. Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis. Sci. Signal. 2016;9:ra64.

    Not in our library10.1126/scisignal.aaf3241

  134. 134.

    Kalinowski D.S., Richardson D.R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev. 2005;57:547-583.

    Not in our library10.1124/pr.57.4.2

  135. 135.

    Dayani P.N., Bishop M.C., Black K., Zeltzer P.M. Desferoxamine (DFO)—Mediated iron chelation: Rationale for a novel approach to therapy for brain cancer. J. Neurooncol. 2004;67:367-377.

    Not in our library10.1023/b:neon.0000024238.21349.37

  136. 136.

    Yu Y., Wong J., Lovejoy D.B., Kalinowski D.S., Richardson D.R. Chelators at the cancer coalface: Desferrioxamine to Triapine and beyond. Clin. Cancer Res. 2006;12:6876-6883.

    Not in our library10.1158/1078-0432.ccr-06-1954

  137. 137.

    Sutherland R., Delia D., Schneider C., Newman R., Kemshead J., Greaves M. Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc. Natl. Acad. Sci. USA. 1981;78:4515-4519.

    Not in our library10.1073/pnas.78.7.4515

  138. 138.

    Hatcher H.C., Singh R.N., Torti F.M., Torti S.V. Synthetic and natural iron chelators: Therapeutic potential and clinical use. Future Med. Chem. 2009;1:1643-1670.

    Not in our library10.4155/fmc.09.121

  139. 139.

    Kontoghiorghes G.J. Ethical issues and risk/benefit assessment of iron chelation therapy: Advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox. Hemoglobin. 2008;32:1-15.

    Not in our library10.1080/03630260701726533

  140. 140.
    Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments · 2014
    No notice
  141. 141.

    Schwoebel F., van Eijk L.T., Zboralski D., Sell S., Buchner K., Maasch C., Purschke W.G., Humphrey M., Zollner S., Eulberg D., et al. The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood. 2013;121:2311-2315.

    Not in our library10.1182/blood-2012-09-456756

  142. 142.

    Kurzrock R., Voorhees P.M., Casper C., Furman R.R., Fayad L., Lonial S., Borghaei H., Jagannath S., Sokol L., Usmani S.Z., et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin. Cancer Res. 2013;19:3659-3670.

    Not in our library10.1158/1078-0432.ccr-12-3349

  143. 143.

    van Rhee F., Fayad L., Voorhees P., Furman R., Lonial S., Borghaei H., Sokol L., Crawford J., Cornfeld M., Qi M., et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J. Clin. Oncol. 2010;28:3701-3708.

    Not in our library10.1200/jco.2009.27.2377

  144. 144.

    Zanganeh S., Hutter G., Spitler R., Lenkov O., Mahmoudi M., Shaw A., Pajarinen J.S., Nejadnik H., Goodman S., Moseley M., et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotechnol. 2016;11:986-994.

    Not in our library10.1038/nnano.2016.168

  145. 145.

    Dezza L., Cazzola M., Danova M., Carlo-Stella C., Bergamaschi G., Brugnatelli S., Invernizzi R., Mazzini G., Riccardi A., Ascari E. Effects of desferrioxamine on normal and leukemic human hematopoietic cell growth: In vitro and in vivo studies. Leukemia. 1989;3:104-107.

    Not in our library

  146. 146.

    Estrov Z., Tawa A., Wang X.H., Dube I.D., Sulh H., Cohen A., Gelfand E.W., Freedman M.H. In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood. 1987;69:757-761.

    Not in our library

  147. 147.

    Donfrancesco A., De Bernardi B., Carli M., Mancini A., Nigro M., De Sio L., Casale F., Bagnulo S., Helson L., Deb G. Deferoxamine followed by cyclophosphamide, etoposide, carboplatin, thiotepa, induction regimen in advanced neuroblastoma: Preliminary results. Italian Neuroblastoma Cooperative Group. Eur. J. Cancer. 1995;31A:612-615.

    Not in our library10.1016/0959-8049(95)00068-t

  148. 148.

    Donfrancesco A., Deb G., Angioni A., Maurizio C., Cozza R., Jenkner A., Landolfo A., Boglino C., Helson L. D-CECaT: A breakthrough for patients with neuroblastoma. Anticancer Drugs. 1993;4:317-321.

    Not in our library10.1097/00001813-199306000-00004

  149. 149.

    Donfrancesco A., Deb G., Dominici C., De Sio L., Inserra A., Boglino C., Takahashi M., Uchino J., Helson L. D-CECaT as preoperative chemotherapy for unresectable neuroblastoma in children over one year of age. Anticancer Res. 1995;15:2347-2350.

    Not in our library

  150. 150.

    Finch R.A., Liu M., Grill S.P., Rose W.C., Loomis R., Vasquez K.M., Cheng Y., Sartorelli A.C. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol. 2000;59:983-991.

    Not in our library10.1016/s0006-2952(99)00419-0

  151. 151.

    Fukushima T., Kawabata H., Nakamura T., Iwao H., Nakajima A., Miki M., Sakai T., Sawaki T., Fujita Y., Tanaka M., et al. Iron chelation therapy with deferasirox induced complete remission in a patient with chemotherapy-resistant acute monocytic leukemia. Anticancer Res. 2011;31:1741-1744.

    Not in our library

  152. 152.

    Kratz F., Muller I.A., Ryppa C., Warnecke A. Prodrug strategies in anticancer chemotherapy. ChemMedChem. 2008;3:20-53.

    Not in our library10.1002/cmdc.200700159

  153. 153.

    Akam E.A., Chang T.M., Astashkin A.V., Tomat E. Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators. Metallomics. 2014;6:1905-1912.

    Not in our library10.1039/c4mt00153b

  154. 154.

    Chang T.M., Tomat E. Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation. Dalton Trans. 2013;42:7846-7849.

    Not in our library10.1039/c3dt50824b

  155. 155.

    Ben-Haim S., Ell P. (18)F-FDG PET and PET/CT in the Evaluation of Cancer Treatment Response. J. Nucl. Med. 2009;50:88-99.

    Not in our library10.2967/jnumed.108.054205

  156. 156.

    Calvaresi E.C., Hergenrother P.J. Glucose conjugation for the specific targeting and treatment of cancer. Chem. Sci. 2013;4:2319-2333.

    Not in our library10.1039/c3sc22205e

  157. 157.

    Akam E.A., Tomat E. Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators. Bioconjug. Chem. 2016;27:1807-1812.

    Not in our library10.1021/acs.bioconjchem.6b00332

  158. 158.

    Younes M., Lechago L.V., Somoano J.R., Mosharaf M., Lechago J. Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res. 1996;56:1164-1167.

    Not in our library

  159. 159.

    Lin Y.-S., Tungpradit R., Sinchaikul S., An F.-M., Liu D.-Z., Phutrakul S., Chen S.-T. Targeting the Delivery of Glycan-Based Paclitaxel Prodrugs to Cancer Cells via Glucose Transporters. J. Med. Chem. 2008;51:7428-7441.

    Not in our library10.1021/jm8006257

  160. 160.

    Liu D.-Z., Sinchaikul S., Vasu P., Reddy G., Chang M.-Y., Chen S.-T. Synthesis of 2′-paclitaxel methyl 2-glucopyranosyl succinate for specific targeted delivery to cancer cells. Bioorg. Med. Chem. Lett. 2007;17:617-620.

    Not in our library10.1016/j.bmcl.2006.11.008

  161. 161.

    Cao J., Cui S., Li S., Du C., Tian J., Wan S., Qian Z., Gu Y., Chen W.R., Wang G. Targeted Cancer Therapy with a 2-Deoxyglucose-Based Adriamycin Complex. Cancer Res. 2013;73:1362-1373.

    Not in our library10.1158/0008-5472.can-12-2072

  162. 162.
    The p53 Tumor Suppressor in the Control of Metabolism and Ferroptosis · 2018
    No notice
  163. 163.

    Jiang L., Kon N., Li T., Wang S.J., Su T., Hibshoosh H., Baer R., Gu W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57-62.

    Not in our library10.1038/nature14344

  164. 164.

    Hangauer M.J., Viswanathan V.S., Ryan M.J., Bole D., Eaton J.K., Matov A., Galeas J., Dhruv H.D., Berens M.E., Schreiber S.L., et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247-250.

    Not in our library10.1038/nature24297

  165. 165.

    Viswanathan V.S., Ryan M.J., Dhruv H.D., Gill S., Eichhoff O.M., Seashore-Ludlow B., Kaffenberger S.D., Eaton J.K., Shimada K., Aguirre A.J., et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453-457.

    Not in our library10.1038/nature23007

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