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Multidrug resistance (MDR) is still a major threat to successful clinical application of cancer chemotherapy. Copper plays an important role in biological systems, and copper is also involved in carcinogenesis. In the present investigation, we addressed the question whether metal copper might be involved in drug resistance of murine and human tumor...
Citations
... Breast cancer patients have been reported to exhibit higher serum and tissue content of copper, with even higher serum copper levels observed in patients non-responsive to chemotherapy (46)(47)(48). The amount of copper-containing cells was positively correlated with tumor growth rate (49). ...
Background:
The role of copper in cancer treatment is multifaceted, with copper homeostasis-related genes associated with both breast cancer prognosis and chemotherapy resistance. Interestingly, both elimination and overload of copper have been reported to have therapeutic potential in cancer treatment. Despite these findings, the exact relationship between copper homeostasis and cancer development remains unclear, and further investigation is needed to clarify this complexity.
Methods:
The pan-cancer gene expression and immune infiltration analysis were performed using the Cancer Genome Atlas Program (TCGA) dataset. The R software packages were employed to analyze the expression and mutation status of breast cancer samples. After constructing a prognosis model to separate breast cancer samples by LASSO-Cox regression, we examined the immune statement, survival status, drug sensitivity and metabolic characteristics of the high- and low-copper related genes scoring groups. We also studied the expression of the constructed genes using the human protein atlas database and analyzed their related pathways. Finally, copper staining was performed with the clinical sample to investigate the distribution of copper in breast cancer tissue and paracancerous tissue.
Results:
Pan-cancer analysis showed that copper-related genes are associated with breast cancer, and the immune infiltration profile of breast cancer samples is significantly different from that of other cancers. The essential copper-related genes of LASSO-Cox regression were ATP7B (ATPase Copper Transporting Beta) and DLAT (Dihydrolipoamide S-Acetyltransferase), whose associated genes were enriched in the cell cycle pathway. The low-copper related genes scoring group presented higher levels of immune activation, better probabilities of survival, enrichment in pathways related to pyruvate metabolism and apoptosis, and higher sensitivity to chemotherapy drugs. Immunohistochemistry staining showed high protein expression of ATP7B and DLAT in breast cancer samples. The copper staining showed copper distribution in breast cancer tissue.
Conclusion:
This study displayed the potential impacts of copper-related genes on the overall survival, immune infiltration, drug sensitivity and metabolic profile of breast cancer, which could predict patients' survival and tumor statement. These findings may serve to support future research efforts aiming at improving the management of breast cancer.
... In vitro and in vivo studies have demonstrated that disulfiram's anticancer activity is dependent on the presence of copper ions [146,147]. Both animal and human studies have shown the elevation of serum copper in individuals with cancer compared to controls [148]. As mentioned previously, disulfiram metabolite diethyldithiocarbamine (DDTC) is a potent metal ion chelator, and the chelation of metal ions leads to the formation of a DDTC-metal ion complex. ...
Background: Since disulfiram’s discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were “disulfiram” and “Antabuse”. Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948–2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a “repurposed” agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.
... 57 Consistently, this study observes the significantly reduced G2/M stage in the cell cycle in both Cu overload and in FOXM1 knockdown embryonic Cu ionophores induced Cu overload is reported to reduce tumor growth and possess anticancer activities, [62][63][64] and induce a distinct form of regulated cell death termed cuproptosis in a 15-to 60-fold increase intracellularly. 29 Meanwhile, some studies have reported that Cu chelators (reducing bioavailable Cu) functioned effectively in the expansion or maintenance of progenitor cells in vitro 65 as well as in patients with lung cancer (a high serum Cu level, >23.6 mM) 66 and with breast cancers (average: 51.2 mM), 67 suggesting Cu bioavailable or not might be the potential differences of system Cu overload in cell proliferation, in cell senescence, or in cell cuproptosis. 50,51 In this study, we observe that Cu ionophore elesclomal co-treated with Cu induces more Cu probe positive fluorescence and more accumulated Cu in HSPCs and the resulted in more reduced percentage of HSPCs in embryos compared with that in Cu single-treated embryos. ...
Unbalanced Cu homeostasis has been suggested to be associated with hematopoietic disease, but the roles of Cu overload in the hematopoietic system and the potential mechanisms are obscure. Here, we report a novel association and the novel potential pathways for Cu overload to induce proliferation defects in zebrafish embryonic hematopoietic stem and progenitor cells (HSPCs) via down-regulating expression of foxm1-cytoskeleton axis, which is conserved from fish to mammals. Mechanistically, we show the direct binding of Cu to transcriptional factors HSF1 and SP1 and that Cu overload induces the cytoplasmic aggregation of proteins HSF1 and SP1. These result in the reduced transcriptional activities of HSF1 and SP1 on their downstream FOXM1 as well as the FOXM1 transcriptional activities on cytoskeletons in HSPCs, which leads to ultimately cell proliferation impairment. These findings unveil the novel linkage of Cu overload with specific signaling transduction as well as the subsequent HSPC proliferation defects.
... Imbalances in copper homeostasis in cells can lead to severe disease in humans, including tumor development (10,11). Excess copper has been linked with various types of cancer, including breast (12)(13)(14), prostate (15)(16)(17), colon (18), lung (19), brain (20), and liver (21) cancer. However, the reasons underlying elevated copper levels in tumors are unclear. ...
Background
Liver hepatocellular carcinoma (HCC) is a prevalent cancer that lacks a sufficiently efficient approach to guide immunotherapy. Additionally, cuproptosis is a recently identified regulated cell death program that is triggered by copper ionophores. However, its possible significance in tumor immune cell infiltration is still unclear.
Methods
Cuproptosis subtypes in HCC were identified using unsupervised consensus cluster analysis based on 10 cuproptosis regulators expressions, and a cuproptosis-related risk signature was generated using univariate and LASSO Cox regression and validated using the ICGC data. Moreover, the relationship between signature and tumor immune microenvironment (TME) was studied through tumor immunotherapy responsiveness, immune cell infiltration, and tumor stem cell analysis. Finally, clinical specimens were analyzed using immunohistochemistry to verify the expression of the three genes in the signature.
Results
Two subtypes of cuproptosis regulation were observed in HCC, with different immune cell infiltration features. Genes expressed differentially between the two cuproptosis clusters in the TCGA were determined and used to construct a risk signature that was validated using the ICGC cohort. Greater immune and stromal cell infiltration were observed in the high-risk group and were associated with unfavorable prognosis. Elevated risk scores were linked with higher RNA stemness scores (RNAss) and tumor mutational burden (TMB), together with a greater likelihood of benefitting from immunotherapy.
Conclusion
It was found that cuproptosis regulatory patterns may play important roles in the heterogeneity of immune cell infiltration. The risk signature associated with cuproptosis can assess each patient’s risk score, leading to more individualized and effective immunotherapy.
... It is worth noting that the accumulation of Cu in the nuclear region has been found in breast cancer cells [54]. Moreover, early reports described the increases of serum Cu in cancer patients, sometimes even correlated with the grade of the cancer [55]. High serum Cu levels were also found in cancer patients resistant to chemotherapy compared to patients responding to treatment [55]. ...
... Moreover, early reports described the increases of serum Cu in cancer patients, sometimes even correlated with the grade of the cancer [55]. High serum Cu levels were also found in cancer patients resistant to chemotherapy compared to patients responding to treatment [55]. However, this remains unexplained up to now, and several data on different types of cancer where published, sometimes being contradictory. ...
Zinc (Zn) is a trace element crucial for oxidative stress, apoptosis, the immune response, and more globally for various processes involved in cellular homeostasis. In some cancers, Zn homeostasis is dysregulated. In this review, the role of Zn in cancer and all the components associated to Zn, the use of Zn and Zn -related proteins as biomarkers and Zn-based strategies for the treatment of tumors will be described. ZIP and ZnT are proteins related to Zn metabolism in normal conditions. In cancer, the level of expression of Zn related proteins is abnormal. These Zn proteins may act as prognostic or diagnostic biomarkers, and may be helpful for detecting early-stage cancers or monitoring the course of the disease. Additionally, Zn and its pathways may also be targeted to treat cancers. Indeed, the use of metals for binding Zn cations allows to regulate the biodistribution of Zn within cells, and will control several downstream signaling pathways. Zinc may also be directly used as a therapeutic substance to improve the prognosis of cancer patients, especially with the supplementation of zinc or the use of Zn oxide nanoparticles.
... On the other, the differential genes between high and low CRGs-score groups showed enrichment in extracellular matrix interaction and focal adhesion function, suggesting an aberrant cell adhesin in high CRGs score samples. Consistent with our reports, Cu concentration was also found to increase in tumor areas and even correlated with the grade of cancer [33][34][35]. High serum Cu levels were also found in cancer patients resistant to chemotherapy compared to patients responding to treatment [35] and promote the scatter and formation of secondary tumors by activating cell proliferation-related enzymes [22]. ...
... Consistent with our reports, Cu concentration was also found to increase in tumor areas and even correlated with the grade of cancer [33][34][35]. High serum Cu levels were also found in cancer patients resistant to chemotherapy compared to patients responding to treatment [35] and promote the scatter and formation of secondary tumors by activating cell proliferation-related enzymes [22]. ...
Esophageal carcinoma (ESCA) is a common type of cancer with high mortality. Cuproptosis is a new type of cell death and is characterized by the dependence on mitochondrial respiration and protein lipoylation. However, the potential roles of cuproptosis-related genes (CRGs) in ESCA remain elusive. Here, we systematically assessed the transcriptional and genetic alterations of CRGs in ESCA. We identified a CRGs signature for ESCA patients. A 6-CRGs signature was constructed by the least absolute shrinkage and selection operator (LASSO) regression analysis along with the univariate cox regression analysis and differential genes analysis. The CRGs score could significantly stratify ESCA patients’ survival and a high CRGs score was significantly correlated with worse overall survival. Moreover, higher CRGs score indicated higher pathology grades and aberrant cell adhesion, possibly via the PI3K-AKT pathway, which could also underly their increased sensitivity to PI3K-AKT pathway inhibitors. In addition, patients with high CRGs tend to hold more mutation load and abnormal APOBEC mutation. Notably, a higher CRGs score was anomalously associated with more immune infiltration, which could explain its malignancy by increased PD-L1 stability and a higher proportion of bystander T cells. In conclusion, our report revealed the significance of cuproptosis in ESCA and may have therapeutic potential in activating the bystander T cells.
... Several efforts have been directed towards developing copper chelation therapies, which have yielded some interesting results. Though a detailed discussion of copper chelation therapy in cancer is beyond the scope of this review, however some interesting developments in the this field include, the discovery that patients refractory to platinum drug based chemotherapy can have copper levels in the serum which go up to 160%, as compared to patients who responded to platinum drug based chemotherapy (Majumder et al., 2009). This brings forth the paradigm that could increase in copper levels be a cause/effect of drug resistance in cancer. ...
Plant derived polyphenolic compounds are considered critical components of human nutrition and have shown chemotherapeutic effects against a number of malignancies. Several studies have confirmed the ability of polyphenols to induce apoptosis and regression of tumours in animal models. However, the mechanism through which polyphenols modulate their malignant cell selective anticancer effects has not been clearly established. While it is believed that the antioxidant properties of these molecules may contribute to lowering the risk of cancer induction by causing oxidative damage to DNA, it could not be held responsible for chemotherapeutic properties and apoptosis induction. It is a well known fact that cellular copper increases within the malignant cell and in serum of patients harboring malignancies. This phenomenon is independent of the cellular origin of malignancies. Based on our own observations and those of others; over the last 30 years our laboratory has shown that cellular copper reacts with plant derived polyphenolic compounds, by a Fenton like reaction, which generates reactive oxygen species and leads to genomic DNA damage. This damage then causes an apoptosis like cell death of malignant cells, while sparing normal cells. This communication reviews our work in this area and lays the basis for understanding how plant derived polyphenols can behave as prooxidants (and not antioxidants) within the microenvironment of a malignancy (elevated copper levels) and gives rationale for their preferential cytotoxicity towards malignant cells.
... High level of Cu in body could increase angiogenesis in cancer and accelerate cancer progression [19,21]. The serum Cu concentrations in breast cancer (average: 51.2 μM), lung cancer (> 23.6 μM), gastrointestinal, and gynecological patients were mostly greater than 20 μM [48][49][50]. Cu chelators inhibit the progression of hepatocellular carcinoma [51], suggesting high serum Cu might be associated with a variety of cancer characterizing with active cell proliferation and angiogenesis. Contrasting starkly with the aforementioned reports, studies unveiled that Cu (CuSO4) at 20 μM in drinking water did not increase the incidence of cancer Content courtesy of Springer Nature, terms of use apply. ...
Molecular transport and cell circulation between tissues and organs through blood and lymphatic vessels are essential for physiological homeostasis in vertebrates. Despite the report of its association with vessel formation in solid tumors, the biological effects of Copper (Cu) accumulation on angiogenesis and lymphangiogenesis during embryogenesis are still unknown. In this study, we unveiled that intersegmental blood circulation was partially blocked in Cu²⁺-stressed zebrafish embryos and cell migration and tube formation were impaired in Cu²⁺-stressed mammalian HUVECs. Specifically, Cu²⁺-stressed embryos showed down-regulation in the expression of amotl2 and its downstream pERK1/2-foxm1-MMP2/9 regulatory axis, and knockdown/knockout of foxm1 in zebrafish embryos phenocopied angiogenesis defects, while FOXM1 knockdown HUVECs phenocopied cell migration and tube formation defects, indicating that excessive Cu²⁺-induced angiogenesis defects and blocked cell migration via down-regulating amotl2-pERK1/2-foxm1-MMP2/9 regulatory axis in both embryos and mammalian cells. Additionally, thoracic duct was revealed to be partially absent in Cu²⁺-stressed zebrafish embryos. Specifically, Cu²⁺-stressed embryos showed down-regulation in the expression of ccbe1 (a gene with pivotal function in lymphangiogenesis) due to the hypermethylation of the E2F7/8 binding sites on ccbe1 promoter to reduce their binding enrichment on the promoter, contributing to the potential mechanisms for down-regulation of ccbe1 and the formation of lymphangiogenesis defects in Cu²⁺-stressed embryos and mammalian cells. These integrated data demonstrate that Cu²⁺ stress impairs angiogenesis and lymphangiogenesis via down-regulation of pERK1/2-foxm1-MMP2/9 axis and epigenetic regulation of E2F7/8 transcriptional activity on ccbe1 expression, respectively.
... The use of a copper chelator is now being investigated as part of a multimodal approach, as it might slow cancer progression and enhance tumor cell sensitivity to other treatments [11,14]. Copper chelators, such as TM, are now being combined with chemotherapeutic agents [14,15], immunotherapy treatments [16,17] or radiotherapy [18]. ...
... The use of a copper chelator is now being investigated as part of a multimodal approach, as it might slow cancer progression and enhance tumor cell sensitivity to other treatments [11,14]. Copper chelators, such as TM, are now being combined with chemotherapeutic agents [14,15], immunotherapy treatments [16,17] or radiotherapy [18]. ...
An emerging target to overcome cancer resistance to treatments is copper, which is upregulated in a wide variety of tumors and may be associated with cancer progression and metastases. The aim of this study was to develop a multimodal ultrasmall nanoparticle, CuPRiX, based on the clinical AGuIX nanoparticle made of the polysiloxane matrix on which gadolinium chelates are grafted. Such hybrid nanoparticles allow: (i) a localized depletion of copper in tumors to prevent tumor cell dissemination and metastasis formation and (ii) an increased sensitivity of the tumor to radiotherapy (RT) due to the presence of high Z gadolinium (Gd) atoms. CuPRiX nanoparticles are obtained by controlled acidification of AGuIX nanoparticles. They were evaluated in vitro on two cancer cell lines (lung and head and neck) using the scratch-wound assay and clonogenic cell survival assay. They were able to reduce cell migration and invasion and displayed radiosensitizing properties.
... Copper is an essential trace element used in all domains of life as a structural component for proteins and as cofactor in catalytic oxidation-reduction (redox) reactions that can result in the production of ROS [288]. Binding of copper (Cu(II), Cu 2+ ) to PrP C facilitates redox balance and copper homeostasis [289] both of which are often disturbed in the TME where cancer drug resistance is associated with higher serum copper levels in patients compared to healthy controls or patients who responded to chemotherapy [290,291]. Copper also changes the conformation of the N-terminal domain [292][293][294][295], which may impede LLPS [121,296] or even prevent the formation of straight β-strands backbone structures in the infectious PrP Sc form when bound to the non-octarepeat peptides (residues 92-96) [297,298]. However, the Cu 2+ inhibition of amyloid formation is dependent upon binding capacity that becomes less effective at a lower pH [93,299], which is characteristic of most TMEs. ...
The unique ability to adapt and thrive in inhospitable, stressful tumor microenvironments (TME) also renders cancer cells resistant to traditional chemotherapeutic treatments and/or novel pharmaceuticals. Cancer cells exhibit extensive metabolic alterations involving hypoxia, accelerated glycolysis, oxidative stress, and increased extracellular ATP that may activate ancient, conserved prion adaptive response strategies that exacerbate multidrug resistance (MDR) by exploiting cellular stress to increase cancer metastatic potential and stemness, balance proliferation and differentiation, and amplify resistance to apoptosis. The regulation of prions in MDR is further complicated by important, putative physiological functions of ligand-binding and signal transduction. Melatonin is capable of both enhancing physiological functions and inhibiting oncogenic properties of prion proteins. Through regulation of phase separation of the prion N-terminal domain which targets and interacts with lipid rafts, melatonin may prevent conformational changes that can result in aggregation and/or conversion to pathological, infectious isoforms. As a cancer therapy adjuvant, melatonin could modulate TME oxidative stress levels and hypoxia, reverse pH gradient changes, reduce lipid peroxidation, and protect lipid raft compositions to suppress prion-mediated, non-Mendelian, heritable, but often reversible epigenetic adaptations that facilitate cancer heterogeneity, stemness, metastasis, and drug resistance. This review examines some of the mechanisms that may balance physiological and pathological effects of prions and prion-like proteins achieved through the synergistic use of melatonin to ameliorate MDR, which remains a challenge in cancer treatment.
