Novel Type of Tetranitrosyl Iron Salt: Synthesis, Structure and Antibacterial Activity of Complex [FeL'2(NO)2][FeL'L"(NO)2] with L'-thiobenzamide and L"-thiosulfate.

In this work a new donor of nitric oxide (NO) with antibacterial properties, namely nitrosyl iron complex of [Fe(C6H5C-SNH2)2(NO)2][Fe(C6H5C-SNH2)(S2O3)(NO)2] composition (complex I), has been synthesized and studied. Complex I was produced by the reduction of the aqueous solution of [Fe2(S2O3)2(NO)2]2- dianion by the thiosulfate, with the further treatment of the mixture by the acidified alcohol solution of thiobenzamide. Based on the structural study of I (X-ray analysis, quantum chemical calculations by NBO and QTAIM methods in the frame of DFT), the data were obtained on the presence of the NO…NO interactions, which stabilize the DNIC dimer in the solid phase. The conformation properties, electronic structure and free energies of complex I hydration were studied using B3LYP functional and the set of 6-31 + G(d,p) basis functions. The effect of an aquatic surrounding was taken into account in the frame of a polarized continuous model (PCM). The NO-donating activity of complex I was studied by the amperometry method using an "amiNO-700" sensor electrode of the "inNO Nitric Oxide Measuring System". The antibacterial activity of I was studied on gram-negative (Escherichia coli) and gram-positive (Micrococcus luteus) bacteria. Cytotoxicity was studied using Vero cells. Complex I was found to exhibit antibacterial activity comparable to that of antibiotics, and moderate toxicity to Vero cells.

Criticality of Surface Characteristics of Intravenous Iron-Carbohydrate Nanoparticle Complexes: Implications for Pharmacokinetics and Pharmacodynamics.

Un-complexed polynuclear ferric oxyhydroxide cannot be administered safely or effectively to patients. When polynuclear iron cores are formed with carbohydrates of various structures, stable complexes with surface carbohydrates driven by multiple interacting sites and forces are formed. These complexes deliver iron in a usable form to the body while avoiding the serious adverse effects of un-complexed forms of iron, such as polynuclear ferric oxyhydroxide. The rate and extent of plasma clearance and tissue biodistribution is variable among the commercially available iron-carbohydrate complexes and is driven principally by the surface characteristics of the complexes which dictate macrophage opsonization. The surface chemistry differences between the iron-carbohydrate complexes results in significant differences in in vivo pharmacokinetic and pharmacodynamic profiles as well as adverse event profiles, demonstrating that the entire iron-carbohydrate complex furnishes the pharmacologic action for these complex products. Currently available physicochemical characterization methods have limitations in biorelevant matrices resulting in challenges in defining critical quality attributes for surface characteristics for this class of complex nanomedicines.

Click ferrocenyl-erlotinib conjugates active against erlotinib-resistant non-small cell lung cancer cells in vitro.

Thanks to development of erlotinib and other target therapy drugs the lung cancer treatment have improved a lot in recent years. However, erlotinib-resistant lung cancer remains an unsolved clinical problem which demands for new therapeutics to be developed. Herein we report the synthesis of a library of 1,4- and 1,5-triazole ferrocenyl derivatives of erlotinib together with their anticancer activity studies against erlotinib-sensitive A549 and H1395 as well as erlotinib-resistant H1650 and H1975 cells. Studies showed that extend of anticancer activity is mainly related to the length of the spacer between the triazole and the ferrocenyl entity. Among the series of investigated compounds two isomers commonly bearing C(O)CH2CH2 spacer have shown superior to erlotinib activity against erlotinib-resistant H1650 and H1975 cells whereas compound with short methylene spacer devoid of any activity. In-depth biological studies for the most active compound showed differences in its mechanism of action in compare to erlotinib. The latter is known EGFR inhibitor whereas their ferrocenyl congener exerts anticancer activity mainly as ROS-inducer which activates mitochondrial pathway of apoptosis in cancer cells. However, docking studies suggested that the most active compound can also binds to the active site of EGFR TK in a similar way as erlotinib.

A CORM loaded nanoplatform for single NIR light-activated bioimaging, gas therapy, and photothermal therapy in vitro.

Carbon monoxide (CO) can cause mitochondrial dysfunction, inducing apoptosis of cancer cells, which sheds light on a potential alternative for cancer treatment. However, the existing CO-based compounds are inherently limited by their chemical nature, such as high biological toxicity and uncontrolled CO release. Therefore, a nanoplatform - UmPF - that addresses such pain points is urgently in demand. In this study, we have proposed a nanoplatform irradiated by near-infrared (NIR) light to release CO. Iron pentacarbonyl (Fe(CO)5) was loaded in the mesoporous polydopamine layer that was coated on rare-earth upconverting nanoparticles (UCNPs). The absorption wavelength of Fe(CO)5 overlaps with the emission bands of the UCNPs in the UV-visible light range, and therefore the emissions from the UCNPs can be used to incite Fe(CO)5 to control the release of CO. Besides, the catechol groups, which are abundant in the polydopamine structure, serve as an ideal locating spot to chelate with Fe(CO)5; in the meantime, the mesoporous structure of the polydopamine layer improves the loading efficiency of Fe(CO)5 and reduces its biological toxicity. The photothermal effect (PTT) of the polydopamine layer is highly controllable by adjusting the external laser intensity, irradiation time and the thickness of the polydopamine layer. The results illustrate that the combination of CO gas therapy (GT) and polydopamine PTT brought by the final nanoplatform can be synergistic in killing cancer cells in vitro. More importantly, the possible toxic side effects can be effectively prevented from affecting the organism, since CO will not be released in this system without near-infrared light radiation.

N-Heterocyclic Carbene Iron Complexes as Anticancer Agents: In Vitro and In Vivo Biological Studies.

Cisplatin and its derivatives are commonly used in chemotherapeutic treatments of cancer, even though they suffer from many toxic side effects. The problems that emerge from the use of these metal compounds led to the search for new complexes capable to overcome the toxic side effects. Here, we report the evaluation of the antiproliferative activity of Fe(II) cyclopentadienyl complexes bearing n-heterocyclic carbene ligands in tumour cells and their in vivo toxicological profile. The in vitro antiproliferative assays demonstrated that complex Fe1 displays the highest cytotoxic activity both in human colorectal carcinoma cells (HCT116) and ovarian carcinoma cells (A2780) with IC50 values in the low micromolar range. The antiproliferative effect of Fe1 was even higher than cisplatin. Interestingly, Fe1 showed low in vivo toxicity, and in vivo analyses of Fe1 and Fe2 compounds using colorectal HCT116 zebrafish xenograft showed that both reduce the proliferation of human HCT116 colorectal cancer cells in vivo.

Iron supplementation for patients undergoing cardiac surgery: a protocol for a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Iron administration has been evaluated in several randomized controlled trials for the potential of increasing baseline hemoglobin values and decreasing the incidence of red blood cell transfusion during cardiac surgery. We describe the protocol for a study aiming to evaluate the efficacy and safety of perioperative iron administration in patients undergoing cardiac surgery. METHODS: We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science, from inception to Nov. 19, 2020, for randomized controlled trials in any language evaluating the perioperative administration of iron in adult patients undergoing cardiac surgery; we will also include the first 50 results from Google Scholar. The primary outcome will be the incidence of red blood cell transfusion from the study intervention time until 8 weeks postoperatively. The secondary outcomes will be the number of red blood cell units transfused; change in ferritin level, reticulocyte count and hemoglobin concentration after iron administration; and adverse events. We will assess the risk of bias with the Cochrane Collaboration Risk of Bias Tool, and will analyze the primary and secondary outcomes using a random-effects model. INTERPRETATION: This study will summarize the current evidence about perioperative iron administration in patients undergoing cardiac surgery, help determine whether this intervention should be included in enhanced-recovery protocols, and shape future research if needed. The final manuscript will be submitted to a peer-reviewed journal. TRIAL REGISTRATION: PROSPERO no. CRD42020161927.

Design and Syntheses of New Antibiotics Inspired by Nature's Quest for Iron in an Oxidative Climate.

This Account describes fundamental chemistry that promoted the discovery of new antibiotics. Specifically, the NH acidity of simple hydroxamic acid derivatives facilitated the syntheses of novel ß-lactams (oxamazins and monobactams), siderophore mimics that limit bacterial iron uptake and bacterially targeted sideromycins (siderophore-antibiotic conjugates). The development of resistance to our current limited set of antibiotic scaffolds has created a dire medical situation. As recently stated, "if you weren't taking antibiotic resistance seriously before, now would be a good time to start." A project commissioned by the British government (https://amr-review.org/) has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 million deaths per year and at least $100 trillion in sacrificed gross national product. The 2020 COVID pandemic confirmed that infectious disease problems are no longer localized but worldwide. Many classical antibiotics, especially ß-lactams, previously provided economical cures, but the evolution of antibiotic destructive enzymes (i.e., ß-lactamases), efflux pumps, and bacterial cell wall permeability barriers has made many types of bacteria, especially Gram-negative strains, resistant. Still, and in contrast to other therapies, the public expectation is that any new antibiotic must be inexpensive. This creates market limitations that have caused most major pharmaceutical companies to abandon antibiotic research. Much needs to be done to address this significant problem.The critical need for bacteria to sequester essential iron provides an Achilles' heel for new antibiotic development. Although ferric iron is extremely insoluble, bacteria need micromolar intracellular concentrations for growth and virulence. To this end, they biosynthesize siderophores (Gr. iron bearer) and excrete them into their environment, where they bind iron with high affinity. The iron complexes are recognized by specific outer-membrane transporters, and once actively internalized, the iron is released for essential processes. To conserve biosynthetic energy, some bacteria recognize and utilize siderophores made by competing strains. As a counter-revolution in the never-ending fight for survival, bacteria have also evolved sideromycins, which are siderophores conjugated to warheads that are lethal to rogue bacteria. While none are now used therapeutically, natural sideromycins called albomycins have been used clinically, and others have been shown to be well tolerated and active in animal infection models. Herein we describe practical methods to synthesize new antibiotics and artificial sideromycins with the generalized structure shown above (siderophore-linker drug). Utilizing the molecular-recognition-based siderophore/sideromycin bacterial assimilation processes, it is possible to design both broad spectrum and exquisitely narrow spectrum (targeted) sideromycins and even repurpose older or more classical antibiotics. Relevant microbiological assays, in vivo animal infection studies, and the recent FDA approval of cefiderocol demonstrate their effectiveness.

Cytotoxicity evaluation of iron nitride nanoparticles for biomedical applications.

Magnetic nanoparticles are widely studied for their use in various therapeutic and diagnostic purposes. As biomaterials, their biocompatibility is as important as their magnetic properties. Iron nitride (Fex Ny ) has excellent magnetic properties, and thus Fex Ny nanoparticles could be useful as potential biomaterials. However, the biocompatibility of Fex Ny nanoparticles is yet to be investigated. In this study, we assessed the biocompatibility of Fex Ny nanoparticles by evaluating their direct-contact cytotoxicity compared with that of magnetite nanoparticles (MNPs). Rat fibroblasts were incubated with the nanoparticle samples dispersed in culture medium at concentrations of 10, 50, and 100 µg/ml. The DNA concentration measurement, MTT assay, and trypan blue exclusion test were conducted after days 1 and 3 of incubation. After day 1, the cell viability decreased, and cell death increased with increasing sample concentration when compared with the control. However, after day 3, there were no significant differences when compared with the control, irrespective of the sample concentrations. Further, there were no significant differences between the Fex Ny nanoparticles and MNPs at the same concentrations in all the cytotoxicity evaluation tests. Therefore, it is suggested that Fex Ny nanoparticles might be as cytocompatible as the conventional MNPs.

Low anticoagulant heparin-iron complex targeting inhibition of hepcidin ameliorates anemia of chronic disease in rodents.

Hepcidin is the only known hormone negatively regulates systemic iron availability, its excess contributes to anemia of chronic disease (ACD).Heparin has been shown to be an efficient hepcidin inhibitor both in vitro and in vivo, but its powerful anticoagulant activity limits this therapeutic application. To this end, heparin-iron complex was prepared by electrostatic interaction and/or coordination between heparin and dihydroxy iron solution ([Fe(OH)2]+) under the condition of ultrasonic assisted. We assessed the anticoagulant activity of heparin-iron in vitro and vivo by sheep plasma, chromogenic substrate method and tail-bleeding in mice, respectively. Anti-hepcidin effect of heparin-iron was detected in HepG2 cell and LPS induced acute inflammation mice by qRT-PCR and ELISA. Turpentine-induced anemia mice were established to evaluate the effect of heparin-iron in ACD. Mice were treated with heparin-iron for 4 weeks. The results indicated that heparin-iron has significantly reduced anticoagulant activity in vitro and in vivo, strongly decreases hepcidin mRNA and IL-6 induced high level of secreted hepcidin in HepG2 cell. Heparin-iron was also found to cause a reduction on hepcidin expression through BMP/SMAD and JAK/STAT3 pathways in LPS induced acute inflammation model in mice. In ACD mice, heparin-iron could lower elevated serum hepcidin and improve anemia. These findings demonstrated low anticoagulant heparin-iron has potential applications for the treatment of ACD with high hepcidin levels.

Comparison of ultrasmall IONPs and Fe salts biocompatibility and activity in multi-cellular in vitro models.

In the paper, the results of the first regular studies of ultra-small iron oxide nanoparticles (IONPs) toxicity in vitro were presented. The influence of PEG-coated NPs with 5 nm magnetite core on six different cell lines was examined. These were: human bronchial fibroblasts, human embryonic kidney cells (HEK293T), two glioblastoma multiforme (GBM) cell lines as well as GBM cells isolated from a brain tumor of patient. Additionally, mouse macrophages were included in the study. The influence of IONPs in three different doses (1, 5 and 25 µg Fe/ml) on the viability, proliferation and migration activity of cells was assessed. Moreover, quantifying the intracellular ROS production, we determined the level of oxidative stress in cells exposed to IONPs. In the paper, for the first time, the effect of Fe in the form of IONPs was compared with the analogical data obtained for iron salts solutions containing the same amount of Fe, on the similar oxidation state. Our results clearly showed that the influence of iron on the living cells strongly depends not only on the used cell line, dose and exposure time but also on the form in which this element was administered to the culture. Notably, nanoparticles can stimulate the proliferation of some cell lines, including glioblastoma multiforme. Compared to Fe salts, they have a stronger negative impact on the viability of the cells tested. Ultra-small NPs, also, more often positively affect cell motility which seem to differ them from the NPs with larger core diameters.

Exosome-Mimetic Supramolecular Vesicles with Reversible and Controllable Fusion and Fission*.

The fusion and fission behaviors of exosomes are essential for the cell-to-cell communication. Developing exosome-mimetic vesicles with such behaviors is of vital importance, but still remains a big challenge. Presented herein is an artificial supramolecular vesicle that exhibits redox-modulated reversible fusion-fission functions. These vesicles tend to fuse together and form large-sized vesicles upon oxidation, undergo a fission process and then return to small-sized vesicles through reduction. Noteworthy, the aggregation-induced emission (AIE) characteristics of the supramolecular building blocks enable the molecular configuration during vesicular transformation to be monitored by fluorescence technology. Moreover, the presented vesicles are excellent nanocarrier candidates to transfer siRNA into cancer cells.

Effects of curcumin complexes on MDA­MB­231 breast cancer cell proliferation.

Curcumin displays anticancer properties; however, some issues with the drug delivery mode limit its therapeutic use. Although reformulation and derivatization of curcumin have improved its bioavailability, curcumin derivatives may not retain the same anticancer properties as the parent compound. The present study investigated the anticancer properties of two curcumin complexes, the iron­curcumin [Fe(Cur)3] and boron­curcumin [B(Cur)2] complexes, in the MDA­MB­231 breast cancer cell line. The cellular localization of curcumin, B(Cur)2 and Fe(Cur)3 was determined by fluorescence microscopy. Cell proliferation, migration and invasion were also analysed. Furthermore, apoptosis­associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription­quantitative PCR. The results demonstrated that the three compounds were localized in the perinuclear and cytoplasmic regions of the cell, and displayed cytotoxicity with IC50 values of 25, 35 and 8 µM for curcumin, B(Cur)2 and Fe(Cur)3, respectively. In addition, the three compounds inhibited cell invasion, whereas only curcumin and B(Cur)2 inhibited cell migration. Furthermore, cell exposure to curcumin resulted in an increase in the relative expression of the two key proapoptotic proteins, cytochrome c and cleaved caspase­3, as well as the antiapoptotic protein haem oxygenase­1. In addition, curcumin increased the expression levels of the voltage­gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin­1 and the calcium channel coding gene calcium voltage­gated channel auxiliary subunit γ4 were increased following exposure to curcumin. Taken together, these results indicated that Fe(Cur)3 and B(Cur)2 may display similar anticancer properties as curcumin, suggesting that chemical complexation may be considered as a strategy for improving the potency of curcumin in the treatment of breast cancer.

Mono-, Di- and Tetra-iron Complexes with Selenium or Sulphur Functionalized Vinyliminium Ligands: Synthesis, Structural Characterization and Antiproliferative Activity.

A series of diiron/tetrairon compounds containing a S- or a Se-function (2a-d, 4a-d, 5a-b, 6), and the monoiron [FeCp(CO){SeC1(NMe2)C2HC3(Me)}] (3) were prepared from the diiron µ-vinyliminium precursors [Fe2Cp2(CO)( µ-CO){ µ-η1: η3-C3(R')C2HC1N(Me)(R)}]CF3SO3 (R = R' = Me, 1a; R = 2,6-C6H3Me2 = Xyl, R' = Ph, 1b; R = Xyl, R' = CH2OH, 1c), via treatment with S8 or gray selenium. The new compounds were characterized by elemental analysis, IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calculations. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compounds (3, 4a-d, 5a-b, 6) display fair to good stability in aqueous media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS production and NADH oxidation studies were carried out on selected compounds to give insights into their mode of action.

Targeted cancer cell delivery of arsenate as a reductively activated prodrug.

Nanoformulations, prodrugs, and targeted therapies are among the most intensively investigated approaches to new cancer therapeutics. Human ferritin has been used extensively as a nanocarrier for the delivery of drugs and imaging agents to cancerous tumor cells both in vitro and in vivo. We report exploitation of the native properties of ferritin, which can be co-loaded with simple forms of iron (FeOOH) and arsenic (arsenate) in place of the native phosphate. The As(III) form arsenic trioxide has been successfully used to treat one blood cancer, but has so far proven too systemically toxic for use on solid tumors in the clinic. The As(V) form, arsenate, on the other hand, while much less systemically toxic upon bolus injection has also proven ineffective for cancer therapy. We extended the C-terminal ends of the human ferritin subunits with a tumor cell receptor targeting peptide and loaded this modified ferritin with ~ 800 arsenates and ~ 1100 irons. Our results demonstrate targeting and uptake of the iron, arsenate-loaded modified human ferritin by breast cancer cells. At the same arsenic levels, the cytotoxicity of the iron, arsenate-loaded human ferritin was equivalent to that of free arsenic trioxide and much greater than that of free arsenate. The iron-only loaded human ferritin was not cytotoxic at the highest achievable doses. The results are consistent with the receptor-targeted human ferritin delivering arsenate as a reductively activated 'prodrug'. This targeted delivery could be readily adapted to treat other types of solid tumor cancers.

High-phosphate induced vascular calcification is reduced by iron citrate through inhibition of extracellular matrix osteo-chondrogenic shift in VSMCs.

BACKGROUND: High serum phosphate (Pi) levels strongly associate with cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients with vascular calcification playing a major role in the pathogenesis of related cardiovascular disease. High-Pi challenged vascular smooth muscle cells (VSMCs) undergo simil-osteoblastic transformation and actively deposit calcium-phosphate crystals. Iron-based Pi-binders are used to treat hyperphosphatemia in CKD patients. METHODS: In this study, we investigated the direct effect of iron citrate on extracellular matrix (ECM) modification induced by high-Pi, following either prophylactic or therapeutic approach. RESULTS: Iron prophylactically prevents and therapeutically blocks high-Pi induced calcification. Masson's staining highlights the changes of muscular ECM that after high-Pi stimulation becomes fibrotic and which modifications are prevented or partially reverted by iron. Interestingly, iron preserves glycogen granules and either prevents or partially reverts the formation of non-glycogen granules induced by high-Pi. In parallel, iron addition is able to either prevent or block the high-Pi induced acid mucin deposition. Iron inhibited calcification also by preventing exosome osteo-chondrogenic shift by reducing phosphate load (0,61 ±â€¯0.04vs0,45 ±â€¯0.05, PivsPi + Fe, p < 0,05, nmol Pi/mg protein) and inducing miRNA 30c (0.62 ± 0.05vs3.07 ±â€¯0.62; PivsPi + Fe, p < 0.01, relative expression). Studying aortic rings, we found that iron significantly either prevents or reverts the high-Pi induced collagen deposition and the elastin decrease, preserving elastin structure (0.7 ± 0.1 vs 1.2 ± 0.1; Pi vs Pi + Fe, p < 0.05, elastin mRNA relative expression). CONCLUSIONS: Iron directly either prevents or partially reverts the high-Pi induced osteo-chondrocytic shift of ECM. The protection of muscular nature of VSMC ECM may be one of the mechanisms elucidating the anti-calcific effect of iron.

A New Approach in Cancer Treatment: Discovery of Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) Complexes as Ferroptosis Inducers.

Chlorido[N,N'-disalicylidene-1,2-phenylenediamine]iron(III) complexes generate lipid-based ROS and induce ferroptosis in leukemia and neuroblastoma cell lines. The extent of ferroptosis on the mode of action is regulated by simple modifications of the substituents at the 1,2-phenylenediamine moiety. In HL-60 cells, the unsubstituted lead exclusively caused ferroptosis. For instance, a 4-F substituent shifted the mode of action toward both ferroptosis and necroptosis, while the analogously chlorinated derivative exerted only necroptosis. Remarkably, cell-death in NB1 neuroblastoma cells was solely induced by ferroptosis, independent of the used substituents. The effects were higher than that of the therapeutically applied drug cisplatin. These data clearly demonstrate for the first time that not only iron ions but also iron salophene complexes are potent ferroptosis inducers, which can be optimized as antitumor agents.

Bacteria-assisted biogreen synthesis of radical scavenging exopolysaccharide-iron complexes: an oral nano-sized nutritional supplement with high in vivo compatibility.

Microbial exopolysaccharides (EPSs) have recently served as an efficient substrate for the production of biocompatible metal nanoparticles (NPs) given their favorable stabilizing and reducing properties due to the presence of polyanionic functional groups in their structure. In the present work, Pantoea sp. BCCS 001 GH was used to produce EPS-stabilized biogenic Fe NPs as a complex through a novel biosynthesis reaction. Physicochemical characterization of the EPS-Fe complex was performed, indicating high thermal stability, desirable magnetic properties due to the uniform distribution of the Fe NPs with the average size of ∼10 nm and spherical shape within the EPS matrix. In addition, the in vivo toxicity of the EPS-stabilized Fe NPs was evaluated to investigate their potential for the treatment of iron deficiency anemia. Biological blood parameters and organ histology studies confirmed very high safety of the biosynthesized composite, making EPS-Fe a suitable candidate with an economical and environment friendly synthesis method for a wide spectrum of potential fields in medicine.

Tris(8-Hydroxyquinoline)iron induces apoptotic cell death via oxidative stress and by activating death receptor signaling pathway in human head and neck carcinoma cells.

BACKGROUND: 8-Hydroxyquinoline derivatives have highly sensitive fluorescent chemosensors for metal ions, which are associated with anti-oxidant, anti-tumor and anti-HIV-1 properties. Head and neck squamous cell carcinoma (HNSCC) is associated with a high rate of mortality and novel anti-HNSCC drugs must be developed. Therefore, effective chemotherapy agents are required to address this public health issue. HYPOTHESIS/PURPOSE: The aim of this study was to investigate the inhibitory effect of tris(8-hydroxyquinoline)iron (Feq3) on the HNSCC and the underlying mechanism. STUDY DESIGN/METHODS: A novel 8-hydroxyquinoline derivative, Feq3, was synthesized. The cell viabilities were analyzed using MTT reagent. Apoptosis and the cell cycle distributions were determined by flow cytometer. Reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, western blot, MitoSOX and CellROX stain assay were used to study the mechanism of Feq3. Feq3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS. RESULTS: Feq3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G2/M phase and the induced arrest of SCC25 cells in the G0/G1 and G2/M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq3 also up-regulated tBid, which interacts with the mitochondrial pathway and tumor necrosis factor-α (TNF-α)/TNF-Rs, FasL/Fas, and TNF-related apoptosis inducing ligand receptors (TRAIL-Rs)/TRAIL-dependent caspases apoptotic signaling pathway in HNSCC cells. However, Feq3 activates Fas but not FasL in SCC25 cells. Feq3 arrests the growth of HNSCC cells and is involved in the mitochondria- and death receptor (DR)-mediated caspases apoptotic pathway. CONCLUSION: This study is the first to suggest that apoptosis mediates the anti-HNSCC of Feq3. Feq3 has potential as a cancer therapeutic agent against HNSCC.

A novel iron(II) phenanthroline complex exhibits anticancer activity against TFR1-overexpressing esophageal squamous cell carcinoma cells through ROS accumulation and DNA damage.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and aggressive cancers worldwide, especially in China, with poor prognosis due to the lack of effective therapeutic strategies. Here, the anticancer effect and pharmacological mechanism of a newly synthesized Fe(II) phenanthroline complex was studied in ESCC. Our data showed that transferrin receptor 1 (TFR1) was specifically overexpressed in ESCC tissues compared to its expression in normal esophageal tissues, a finding further supported by public datasets. The newly synthesized Fe(II) complex was selectively transported into ESCC cells overexpressing TFR1 through TFR1-mediated endocytosis and exhibited anticancer activity in a dose-dependent manner. The mechanistic study elucidated that the Fe(II) complex caused cell cycle arrest at the G0/G1 phase by blocking the CDK4/6-cyclin D1 complex and induced mitochondria-mediated apoptosis. Furthermore, exposure to the Fe(II) complex led to excessive reactive oxygen species (ROS) accumulation by thioredoxin reductase (TrxR) inhibition and DNA double-strand breaks (DSBs), which in turn sequentially activated ATM, CHK1/2 and p53. Moreover, combination treatment with cisplatin and the Fe(II) complex exhibited a synergistic effect in ESCC cells. Taken together, our results initially suggest the potential application of the Fe(II) complex in ESCC chemotherapy, especially for patients with TFR1 overexpression.

Potential role of MRN-100, an iron-based compound, in upregulating production of cytokine IL-10 in human dendritic cells to promote an anti-inflammatory response in vitro.

The hydroferrate fluid MRN-100, an iron-based compound with potent antioxidant characteristics, was examined to identify its possible anti-inflammatory effects on human dendritic cells (DCs) in vitro. Human monocyte-derived DCs were treated with MRN-100 at two concentrations (50 and 100 µL/mL) for 24 h and then stimulated with or without lipopolysaccharides (LPS). The expression of DC maturation markers was assessed by flow cytometry and the production of cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Functional assay was performed by co-culturing MRN-100-treated and untreated DCs with allogeneic naïve CD4+ T cells and assaying the T cells' cytokine production. Results show that treatment with MRN-100 significantly upregulated the co-stimulatory molecules CD80 and CD86 and increased human leukocyte antigen-DR (HLA-DR) though not significantly. MRN-100 treatment also significantly increased the production of the anti-inflammatory cytokine interleukin (IL)-10. On the other hand, MRN-100 significantly induced the secretion of pro-inflammatory cytokines such as IL-6 only at high concentrations. Furthermore, DCs pretreated with MRN-100 and either stimulated or not with LPS were able to prime CD4+ T cells to secrete significant amounts of IL-10 while inhibiting the secretion of pro-inflammatory cytokine tumor necrosis factor (TNF)-α. These results indicate that MRN-100 is a powerful anti-inflammatory agent that promotes the generation of an anti-inflammatory immune response in vitro. MRN-100 could be beneficial for treating patients with inflammatory diseases, including arthritis and type 1 diabetes, and its potential benefits should be examined in clinical trials.