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Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.

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In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-ß (Aß) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aß-Cu2+ complex as Aß peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine. These SB compounds contain one copper chelating core, which captures the Cu2+ ions from the Aß-Cu2+ complex. Thereby, it inhibits copper-induced amyloid aggregation as well as amyloid self-aggregation. It also inhibits copper-catalyzed ROS production through sequestering of Cu2+ ions. The uniqueness of our designed ligands has the dual property of dopamine, which not only acts as a ROS scavenger but also chelates the copper ion. The crystallographic analysis proves the power of the dopamine unit. Therefore, dual exploration of dopamine core can be considered as potential therapeutics for future AD treatment.

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Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking the dynamic copper concentrations inside cells. Copper homeostasis is disrupted in neurological diseases like Alzheimer's disease, and copper forms aggregates with amyloid beta (Ab42) peptide, resulting in senile plaques in Alzheimer's brains. Therefore, a selective copper detector probe that can detect amyloid beta peptide-copper aggregates and decrease the aggregate size has potential uses in medicine. We have developed a series of Cu2+-selective low fluorescent to high fluorescent tri and tetradentate dentate ligands and conjugated them with a peptide ligand to amyloid-beta binding peptide to increase the solubility of the compounds and make the resultant compounds bind to Cu2+-amyloid aggregates. The copper selective compounds were developed using chemical scaffolds known to have high affinity and selectivity for Cu2+, and their conjugates with peptides were tested for affinity and selectivity towards Cu2+. The test results were used to inform further improvement of the next compound. The final Cu2+ chelator-peptide conjugate we developed showed high selectivity for Cu2+ and high fluorescence properties. The compound bound 1:1 to Cu2+ ion, as determined from its Job's plot. Fluorescence of the ligand could be detected at nanomolar concentrations. The effect of this ligand on controlling Cu2+-Ab42 aggregation was studied using fluorescence assays and microscopy. It was found that the Cu2+-chelator-peptide conjugate efficiently reduced aggregate size and, therefore, acted as an inhibitor of Ab42-Cu2+ aggregation. Since high micromolar concentrations of Cu2+ are present in senile plaques, and Cu2+ accelerates the formation of toxic soluble aggregates of Ab42, which are precursors of insoluble plaques, the developed hybrid molecule can potentially serve as a therapeutic for Alzheimer's disease.

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Radiation therapy is a first-line treatment for head and neck cancer; however, it typically leads to hyposalivation stemming from fibrosis of the salivary gland. Current strategies to restore glandular function are dependent on the presence of residual functional salivary gland tissue, a condition commonly not met in patients with extensive fibrotic coverage of the salivary gland resulting from radiation therapy. Fibrosis is defined by the pathological accumulation of connective tissue (i.e., extracellular matrix) and excessive deposition of crosslinked (fibrillar) collagen that can impact a range of tissues and given that collagen crosslinking is necessary for fibrosis formation, inhibiting this process is a reasonable focus for developing anti-fibrotic therapies. Collagen crosslinking is catalyzed by the lysyl oxidase family of secreted copper-dependent metalloenzymes, and since that copper is an essential cofactor in all lysyl oxidase family members, we tested whether localized delivery of a copper chelator into the submandibular gland of irradiated mice could suppress collagen deposition and preserve the structure and function of this organ. Our results demonstrate that transdermal injection of tetrathiomolybdate into salivary glands significantly reduced the early deposition of fibrillar collagen in irradiated mice and preserved the integrity and function of submandibular gland epithelial tissue. Together, these studies identify copper metabolism as a novel therapeutic target to control radiation induced damage to the salivary gland and the current findings further indicate the therapeutic potential of repurposing clinically approved copper chelators as neoadjuvant treatments for radiation therapy.

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(1) Background: In patients with Wilson's disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in "toxic milk" TX mice as an oral treatment of this Wilson's disease murine model; (3) Results: The concentration of copper in the liver of "toxic milk" TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson's disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease.

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Background: Hepatocellular carcinoma (HCC) is one of the main cancer-related mortality worldwide. Thus, there is a constant search for improvement in treatment strategies to enhance the prognosis of this malignancy. The study aims to investigate the combined antitumor activity of ammonium tetrathiomolybdate (TM, copper chelator) combined with hepatic artery ligation (HAL) for liver cancer. Methods: A total of 40 Sprague-Dawley (SD) rats bearing hepatic tumors were randomly divided into four groups: the control group without any treatment (control), HAL only (HAL), given TM by gavage (TM), and given TM combined with HAL (HAL + TM). The concentrations of serum copper were measured at the predetermined time points. Tumor growth rate, overall survival (OS), expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microvessel density (MVD), as determined by immunohistochemical examination, were compared. Results: HAL treatment transiently could elevate alanine transaminase (ALT) and aspartate transaminase (AST) but resumed to baseline within 1 week. Serum copper was significantly increased in tumor-bearing animals over time. The values of serum copper in the three treatment groups were significantly lower than those in the control group at different time points, with the lowest values observed in the TM group (P < .05). The average tumor size was 30.33 ± 2.58, 20.83 ± 2.93, 16.80 ± 3.84, and 10.88 ± 1.08 mm in the control, HAL, TM, and HAL + TM groups, respectively (HAL + TM vs other groups, all P < .05). In addition, the expression levels of HIF-1α, VEGF, and MVD were significantly lower in the HAL + TM group than those in the other groups (P < .05). The OS of rats in the combined groups was significantly prolonged combined to the other groups (P < .05), with survival time of 19.1 ± 0.64, 25.4 ± 1.24, 25.3 ± 1.78, and 29.9 ± 2.22 days in the control, HAL, TM, and HAL + TM groups, respectively. Conclusion: These findings suggest that combined treatment with TM and HAL holds great potential for liver cancer treatment by reducing tumor hypoxia and angiogenesis. The observed results indicate that these combinations may offer a novel target and strategy for interventional therapy of liver cancer.

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Copper is an essential trace metal for normal cellular functions; a lack of copper is reported to impair the function of important copper-binding enzymes, while excess copper could lead to cell death. Numerous studies have shown an association between dietary copper consumption or plasma copper levels and the incidence of diabetes/diabetes complications. And experimental studies have revealed multiple signaling pathways that are triggered by copper shortages or copper overload in diabetic conditions. Moreover, studies show that treated with copper chelators improve vascular function, maintain copper homeostasis, inhibit cuproptosis, and reduce cell toxicity, thereby alleviating diabetic neuropathy, retinopathy, nephropathy, and cardiomyopathy. However, the mechanisms reported in these studies are inconsistent or even contradictory. This review summarizes the precise and tight regulation of copper homeostasis processes, and discusses the latest progress in the association of diabetes and dietary copper/plasma copper. Further, the study pays close attention to the therapeutic potential of copper chelators and copper in diabetes and its complications, and hopes to provide new insight for the treatment of diabetes.

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Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called "JYFY-001" that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRC-transplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice. Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.

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PURPOSE: The study aims to investigate the suppressing tumor-promoting effects via multi-anti-angiogenesis activity of the copper chelator (ammonium tetrathiomolybdate, TM) combined with lenvatinib for hepatocellular carcinoma. METHODS: A total of 55 C57 mice were injected subcutaneously with Hepa1-6 hepatoma cell suspensions into the right posterior thigh. After 7 days, the subcutaneous tumors were formed, and the mice were randomly divided into five groups: TM (G1), Lenvatinib (G2), TM+Lenvatinib (G3), Control (G4), and Copper (II) Gluconate (G5). The copper concentrations in serum and tumors were measured at the predetermined time points. After 14 days of treatments, tumor weight and volumes were analyzed, histology was observed, and the expressions of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in tumor tissues were measured by immunohistochemistry. RESULTS: The median concentration of copper in serum was 401.70, 469.40, and 665.35 µg/L in normal mice, in mice 7 days after implantation, and in the control group, respectively. The intratumoral copper concentrations were higher in G4 mice than in mice 7 days after implantation (P < 0.05). The serum concentration of copper was higher in G5 than all the other groups (P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G2, P = 0.013; G2 vs. G3, P = 0.018; G1 vs. G3, P = 0.903. The intratumoral copper concentrations were 608.40, 980.00, 539.31, and 2938.90 µg/L in G1, G2, G3, and G5, respectively. The average tumor weight was 0.55, 0.44, 0.08, 1.37, and 3.11 in G1, G2, G3, G4, and G5, respectively. G5 vs. other groups, P < 0.05; (G1, G2, and G3) vs. G4, P < 0.05; G1 vs. G3, P < 0.05; G2 vs. G3, P < 0.05; G1 vs. G2, P > 0.05. Furthermore, the expression levels of VEGF were significantly lower in G1, G2, and G3 than in G4 and G5 (P < 0.05). A similar trend was observed for MVD in the five groups, but no significant difference was detected in G1 and G2. CONCLUSION: The study showed a significant positive correlation between tumor load and copper. Copper promotes tumor progression, but copper chelating suppresses tumor growth. The combination of TM with lenvatinib reduces tumor angiogenesis and improves the effect of antitumor treatment. These findings underlie the clinical application of combination therapy.

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(1) Background: TDMQ20 is a specific regulator of copper homeostasis in the brain, able to inhibit cognitive impairment in the early stages of Alzheimer's disease (AD) in mouse models of AD. To promote the further development of this drug-candidate, preliminary data on the pharmacokinetics of TDMQ20 in a mammal model have been collected. Since TDMQ20 should be administered orally, its absorption by the gastrointestinal tract was evaluated by comparison of blood concentrations after administration by oral and IV routes, and its ability to reach its target (the brain) was confirmed by comparison between blood and brain concentrations after oral administration. (2) Methods: plasmatic and brain concentrations of the drug after oral or intravenous treatment of rats at pharmacologically relevant doses were determined as a function of time. (3) Results: oral absorption of TDMQ20 was rapid and bioavailability was high (66% and 86% for males and females, respectively). The drug accumulated in the brain for several hours (brain-plasma ratio 3 h after oral administration = 2.6), and was then efficiently cleared. (4) Conclusions: these data confirm that TDMQ20 efficiently crosses the brain-blood barrier and is a relevant drug-candidate to treat AD.

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The synthesis of hydrogels that are based on poly-hydroxyethyl methacrylate, p(HEMA), network semi-interpenetrated with linear polyvinylpyrrolidone (PVP) was optimized in order to allow both a fast preparation and a high cleaning effectiveness of artistic surfaces. For this purpose, the synthesis parameters of the gel with PVP having a high molecular weight (1300 kDa) that were reported in the literature, were modified in terms of temperature, time, and crosslinker amount. In addition, the gel composition was modified by using PVP with different molecular weights, by changing the initiator and by adding maleic anhydride. The modified gels were characterized in terms of equilibrium water content (EWC), water uptake, conversion grade, and thermal properties by differential scanning calorimetry (DSC). The cleaning effectiveness of the gels was studied through the removal of copper salts from laboratory-stained specimens. Cleaning materials were characterized by electron paramagnetic resonance (EPR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, and inductively-coupled plasma-mass spectrometry (ICP-MS). Cleaning was assessed on marble specimens by color variation measurements. The gel synthesis is accelerated by using PVP 360 kDa. The addition of maleic anhydride in the p(HEMA)/PVP network allows the most effective removal of copper salt deposits from marble since it acts as a chelator towards copper ions.

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The interaction between copper ions and amyloid peptide Aß has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aß complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aß1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

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BACKGROUND: Cisplatin-based chemotherapy is the standard treatment for non-small cell lung cancer (NSCLC). However, cisplatin resistance is a major obstacle to successful therapeutic efficacy. Novel therapeutic strategies are urgently needed to reverse chemotherapy resistance and improve prognosis. In the present study, we aimed to investigate whether copper chelator Tetrathiomolybdate (TM) can enhance the anticancer effect of cisplatin, and elucidate the underlying mechanisms. METHODS: Cell viability, wounding healing, and colony formation assays were performed on H1299 and A549 cells. The combination indices (CI) were determined by the Chou-Talalay method. Flow cytometry was used to detect cell apoptosis and ROS generation. GSH levels were measured in a microplate reader. RNA-seq and bioinformatics analyses were used to analyze the differentially expressed genes (DEGs) and enriched biology processes. The concentrations of Pt and Cu were determined by ICP-MS. Animal xenograft tumor model was established to evaluate the synergistic anticancer effect of TM and cisplatin. RESULTS: Combination treatment with TM and cisplatin decreased cell viability and migration of H1299 and A549 cells compared with cisplatin alone. Mechanistically, combination treatment could significantly increase ROS and reduce GSH content, leading to a notable increase in DNA-bound Pt and cell apoptosis. Moreover, in animal xenograft tumor model, TM enhanced cisplatin-elicited antitumor effect, but did not increase cisplatin-induced side effects. CONCLUSION: Our study suggests that TM may be a promising chemotherapeutic sensitizer for non-small cell lung cancer.

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Copper homeostasis is finely regulated in human to avoid any detrimental impact of free intracellular copper ions. Upon copper accumulation, biliary excretion is triggered in liver thanks to trafficking of the ATP7B copper transporter to bile canaliculi. However, in Wilson's disease this protein is mutated leading to copper accumulation. Current therapy uses Cu chelators acting extracellularly and requiring a life-long treatment with side effects. Herein, a new Cu(I) pro-chelator was encapsulated in long-term stable nanostructured lipid carriers. Cellular assays revealed that the pro-chelator protects hepatocytes against Cu-induced cell death. Besides, the cellular stresses induced by moderate copper concentrations, including protein unfolding, are counteracted by the pro-chelator. These data showed the pro-chelator efficiency to deliver intracellularly an active chelator that copes with copper stress and surpasses current and under development chelators. Although its biological activity is more mitigated, the pro-chelator nanolipid formulation led to promising results. This innovative approach is of outmost importance in the quest of better treatments for Wilson's disease.

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The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.

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Suitable in vivo and in vitro models are instrumental for the development of new drugs aimed at improving symptoms or progression of multiple sclerosis (MS). The cuprizone (CPZ)-induced murine model has gained momentum in recent decades, aiming to address the demyelination component of the disease. This work aims at assessing the differential cytotoxicity of CPZ in cells of different types and from different species: human oligodendroglial (HOG), human neuroblastoma (SH-SY5Y), human glioblastoma (T-98), and mouse microglial (N-9) cell lines. Moreover, the effect of CPZ was investigated in primary rat brain cells. Cell viability was assayed by oxygen rate consumption and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based (MTT) method. Our results demonstrated that CPZ did not cause death in any of the assayed cell models but affected mitochondrial function and aerobic cell respiration, thus compromising cell metabolism in neural cells and neuron-glia co-cultures. In this sense, we found differential vulnerability between glial cells and neurons as is the case of the CPZ-induced mouse model of MS. In addition, our findings demonstrated that reduced viability was spontaneous reverted in a time-dependent manner by treatment discontinuation. This reversible cell-based model may help to further investigate the role of mitochondria in the disease, and study the molecular intricacies underlying the pathophysiology of the MS and other demyelinating diseases.

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BACKGROUND: Ceruloplasmin (Cp) is a major copper-binding protein produced in the liver and delivers copper to extrahepatic organs. Patients with myocardial infarction are often featured by an elevation of serum copper concentrations due to copper efflux from ischemic hearts. The present study was undertaken to test the hypothesis that serum copper elevation leads to up-regulation of hepatic Cp in myocardial infarction. METHODS: Adult male Sprague-Dawley rats were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial infarction. Serum copper and Cp levels, as well as changes in hepatic Cp and copper-transporting P-type ATPase (Atp7b), were determined from blood and liver samples collected on day 1, 4, or 7 after the operation. RESULTS: Serum copper concentrations were significantly increased on day 4 after LAD ligation, accompanied by an increase in serum Cp levels and activities. Concomitantly, the protein levels of Cp and copper exporter, Atp7b, were also significantly increased in the liver. Furthermore, inhibiting the increase of serum copper by a copper chelator, triethylenetetramine (TETA), effectively abolished the elevated Cp activity after LAD ligation. CONCLUSION: These results indicate that serum Cp elevation in response to myocardial ischemia most likely resulted from the increased hepatic Cp production, which in turn was more responsive to serum copper elevation than inflammatory response following myocardial ischemia.

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Copper plays an important role in tumor growth and metastasis. Copper chelation has been confirmed to be an effective strategy for breast cancer therapy through antiangiogenesis. In this work, a copper chelating coil-comb block copolymer RGD-PEG-b-PGA-g-(TETA-DTC-PHis) (RPTDH) was synthesized and used to prepare nanoparticles for loading resiquimod (R848), a TLR7 and TLR8 agonist, thus to combine antiangiogenesis and immune activation to treat breast cancer. RPTDH has strong copper-chelating ability and could self-assemble to form spherical nanoparticles with significant pH-sensitivity. R848 was efficiently loaded into RPTDH nanoparticles and exhibited greatly accelerated releases in weakly acid media simulating tumor microenvironment. RPTDH/R848 nanoparticles significantly inhibited the mobility, invasion and vascular tube formation of HUVECs via copper chelation, demonstrating their strong antiangiogenic activity in vitro. Furthermore, RPTDH/R848 nanoparticles remarkably induced the maturation and activation of human plasmacytoid dendritic CAL-1 cells, indicating their immune-activation ability. In breast tumor-bearing mice, RPTDH/R848 nanoparticles displayed excellent targeting ability for both primary breast tumor and lung metastases, and furthermore dramatically suppressed tumor growth and metastasis through copper deficiency-triggered antiangiogenesis and R848-induced immune activation. In summary, RPTDH/R848 nanoparticles can be used as an therapeutic agent against metastatic breast cancer through combining antiangiogenesis and immune activation.

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In this work, we aim to provide evidence for the protective effect of a copper chelator, neocuproine (NeoCu), against the oxidative stress in NSC34 cells, which inhibits biomolecule oxidation and cell death. Results obtained with the comet assay allowed to determine the increase in oxidized purines and pyrimidines by H2O2 exposure, and their changes after the addition of NeoCu. We also observed a higher ATP7b activity in nuclei and a higher Cu concentration inside the cells, proving that the NeoCu acts directly in DNA to promote cell recovery in oxidative stress conditions, also observed in Reactive Oxygen Species (ROS) detection assay by Flow Cytometry. Based on these results, we propose that NeoCu is a promising drug for the protection of motor neuron cells during oxidative stress caused by neurodegenerative diseases in this system.

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Copper is essential for the generation of reactive oxygen species (ROS), which are induced by amyloid-ß (Aß) aggregation; thus, the homeostasis of copper is believed to be a therapeutic target for Alzheimer's disease (AD). Although clinical trials of copper chelators show promise when applied in AD, the underlying mechanism is not fully understood. Here, we reported that copper chelators promoted nonamyloidogenic processing of AßPP through MT1/2 /CREB-dependent signaling pathways. First, we found that the formation of Aß plaques in the cortex was significantly reduced, and learning deficits were significantly improved in AßPP/PS1 transgenic mice by copper chelator tetrathiomolybdate (TM) administration. Second, TM and another copper chelator, bathocuproine sulfonate (BCS), promoted nonamyloidogenic processing of AßPP via inducing the expression of ADAM10 and the secretion of sAßPPα. Third, the inducible ADAM10 production caused by copper chelators can be blocked by a melatonin receptor (MT1/2 ) antagonist (luzindole) and a MT2 inhibitor (4-P-PDOT), suggesting that the expression of ADAM10 depends on the activation of MT1/2 signaling pathways. Fourth, three of the MT1/2 -downstream signaling pathways, Gq/PLC/MEK/ERK/CREB, Gs/cAMP/PKA/ERK/CREB and Gs/cAMP/PKA/CREB, were responsible for copper chelator-induced ADAM10 production. Based on these results, we conclude that copper chelators regulate the balance between amyloidogenic and nonamyloidogenic processing of AßPP via promoting ADAM10 expression through MT1/2 /CREB-dependent signaling pathways.

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