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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)CH 2 CH 2 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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 IC 50 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.

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 iron‑curcumin [Fe(Cur)3] and boron‑curcumin [B(Cur)2] complexes, in the MDA‑MB‑231 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, apoptosis‑associated proteins were detected by using a proteome profiler array, and ion channel gene expression was analysed by reverse transcription‑quantitative 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 caspase‑3, as well as the antiapoptotic protein haem oxygenase‑1. In addition, curcumin increased the expression levels of the voltage‑gated potassium channels Kv2.1 and Kv3.2. Similarly, the expression levels of the chloride channel bestrophin‑1 and the calcium channel coding gene calcium voltage‑gated 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.

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.

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){SeC 1 (NMe 2 )C 2 HC 3 (Me)}] ( 3 ) were prepared from the diiron μ-vinyliminium precursors [Fe 2 Cp 2 (CO)( μ-CO){ μ-η 1 : η 3 -C 3 (R')C 2 HC 1 N(Me)(R)}]CF 3 SO 3 (R = R' = Me, 1a ; R = 2,6-C 6 H 3 Me 2 = Xyl, R' = Ph, 1b ; R = Xyl, R' = CH 2 OH, 1c ), via treatment with S 8 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.

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 (Feq 3 ) on the HNSCC and the underlying mechanism., Study Design/methods: A novel 8-hydroxyquinoline derivative, Feq 3 , 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 Feq 3 . Feq 3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS., Results: Feq 3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq 3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G 2 /M phase and the induced arrest of SCC25 cells in the G 0 /G 1 and G 2 /M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq 3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq 3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq 3 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, Feq 3 activates Fas but not FasL in SCC25 cells. Feq 3 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 Feq 3 . Feq 3 has potential as a cancer therapeutic agent against HNSCC., (Copyright © 2019. Published by Elsevier GmbH.)

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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Therapeutic nanosystems which can be triggered by the distinctive tumor microenvironment possess great selectivity and safety to treat cancers via in situ transformation of nontoxic prodrugs into toxic therapeutic agents. Here, we constructed intelligent, magnetic targeting, and tumor microenvironment-responsive nanocatalysts that can acquire oxidation therapy of cancer via specific reaction at tumor site. The magnetic nanoparticle core of iron carbide-glucose oxidase (Fe 5 C 2 -GOD) achieved by physical absorption has a high enzyme payload, and the manganese dioxide (MnO 2 ) nanoshell as an intelligent "gatekeeper" shields GOD from premature leaking until reaching tumor tissue. Fe 5 C 2 -GOD@MnO 2 nanocatalysts maintained inactive in normal cells upon systemic administration. On the contrary, after endocytosis by tumor cells, tumor acidic microenvironment induced decomposition of MnO 2 nanoshell into Mn 2+ and O 2 , meanwhile releasing GOD. Mn 2+ could serve as a magnetic resonance imaging (MRI) contrast agent for real-time monitoring treatment process. Then the generated O 2 and released GOD in nanocatalysts could effectively exhaust glucose in tumor cells, simultaneously generating plenty of H 2 O 2 which may accelerate the subsequent Fenton reaction catalyzed by the Fe 5 C 2 magnetic core in mildly acidic tumor microenvironments. Finally, we demonstrated the tumor site-specific production of highly toxic hydroxyl radicals for enhanced anticancer therapeutic efficacy while minimizing systemic toxicity in mice.

Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.

Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5μM (ca. 300μg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity., (Copyright © 2015. Published by Elsevier B.V.)

Four new compounds of general formula [FeCp(dppe)L][CF3SO3] with L=imidazole substituted ligands, and dppe=ethylenebis(diphenylphosphane) have been synthesized and characterized with the aim to evaluate their anticancer properties. The new compounds were fully characterized by spectroscopic and electrochemical methods and the structure of [Fe(η(5)-C5H5)(dppe)(1-BuIm)] [CF3SO3] (1), [Fe(η(5)-C5H5)(dppe) (ImH)][CF3SO3] (3) and [Fe(η(5)-C5H5)(dppe)(1HmIm)][CF3SO3] (4) (where 1-BuIm=1-butylimidazole, and 1HmIm=N-hydroxymethylimidazole) was determined by X-ray diffraction studies. Apparently, these compounds are the first reported 'Fe(η(5)-C5H5)' half sandwich derivatives presenting high cytotoxic activity against a set a human tumor cell lines predicting their potential value as antitumor drugs., (© 2013.)

Background: Over the last few decades, metal-based drugs, particularly cisplatin and its analogs have been used for the treatment of various cancers. Currently, scientists are developing other metal complexes as anticancer agents to eliminate the toxicity associated with platinum drugs., Results: Claisen-Schmidt condensation was used to synthesize the pyrazoline-based ligand; (5-(4-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide), followed by the synthesis of its complexes with copper(II), nickel(II) and iron(III) metal ions. DNA binding and in silico studies indicated quite good binding with DNA; requirements for good anticancer drugs., Conclusion: DNA binding constants for ligand, copper, nickel and iron complexes were 1.42 × 10(4), 3.16 × 10(4), 5.82 × 10(5) and 6.72 × 10(5) M(-1), respectively, indicating strong binding with DNA. All the reported compounds were slightly hemolytic towards rabbit red blood corpuscles and exhibited moderate activities against MCF-7 cancer cell lines.

The iron(II) complexes and with pentadentate pyridyl ligands are stable under physiological conditions and exhibit higher cytotoxicities toward a series of human carcinoma cell lines than cisplatin; can significantly increase intracellular oxidant levels, cleave supercoiled plasmid DNA in vitro without addition of a reductant and induce apoptotic cell death in human cervical epithelioid carcinoma cells (HeLa) as observed in flow cytometric studies.

The antitumor activities of some Fe(II)/Fe(III) complexes containing 1,3-diacetyl-2H-benzimidazole-2-thione along with a few derivatives of 1,2,4-triazol, 1,3,4-oxadiazole and 1,3,4-thiadiazole as co-ligands have been investigated. Antibacterial and antifungal activities of disulfido-/dichloro-bridged dinuclear Fe(III)/Fe(II) complexes containing similar heterocycles as terminal ligands have also been investigated.