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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
... The main challenge affecting its therapeutic efficacy is chemotherapy resistance, which is one of the main reasons for the failure of anti-cancer treatments (225). Unlike exogenous platinum drugs that often lead to the upregulation of glutathione (GSH) stress in tumor cells and thus lead to chemotherapy resistance in tumor patients, a team of researchers has found that Diethyldithiocarbamic Acid Copper Salt (CuET) reverses cisplatin resistance in non-small-cell lung cancer through a cuproptosis mechanism (226). They also bring new inspiration for inducing cuproptosis in GC to achieve the reversal of platinum drug resistance (227). ...
As a biologically essential transition metal, copper is widely involved in various enzymatic reactions and crucial biological processes in the body. It plays an increasingly important role in maintaining normal cellular metabolism and supporting the growth and development of the human body. As a trace element, copper maintains the dynamic balance of its concentration in body fluids through active homeostatic mechanisms. Both excess and deficiency of copper ions can impair cell function, ultimately leading to cell damage and death. Cuproptosis is a novel form of cell death where copper ions cause cell death by directly binding to the lipoylated components of the citric acid cycle (CAC) in mitochondrial respiration and interfering with the levels of iron-sulfur cluster (Fe-S cluster) proteins, ultimately causing protein toxic stress. Its primary characteristics are Cu2+ concentration dependence and high expression in mitochondrial respiratory cells. Recent research has revealed that, compared to other forms of programmed cell death such as apoptosis, necrosis, and autophagy, cuproptosis has unique morphological and biochemical features. Cuproptosis is associated with the occurrence and development of various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases. This article focuses on a review of the relevance of cuproptosis in gastric cancer (GC).
... Emerging evidence suggests that copper ion transport mechanisms could be implicated in drug resistance [ 94 ]. Majumder et al. [ 95 ] investigated the correlation between copper ion levels and drug resistance to identify patients resistant to treatment, aiming to develop improved therapeutic strategies. They revealed that blood serum from tumorbearing mice displayed increased copper ion levels compared to healthy normal mice. ...
The recent discovery of cuproptosis, a novel copper-ion-induced cell death pathway, has suggested the novel therapeutic potential for treating heterogeneous and drug-resistant cancers. Currently, copper ionophore-based therapeutics have been designed to treat cancers, utilizing copper ions as a strategic tool to impede tumor proliferation and promote cellular demise. However, limitations of copper ionophore-based therapies include nontargeted delivery of copper ions, low tumor accumulation, and short half-life. Strategies to enhance specificity involve targeting intracellular cuproptosis mechanisms using nanotechnology-based drugs. Additionally, the importance of exploring combination therapies cannot be overstated, as they are a key strategy in improving the efficacy of cancer treatments. Recent studies have reported the anticancer effects of nanomedicines that can induce cuproptosis of cancer both in vitro and in vivo. These cuproptosis-targeted nanomedicines could improve delivery efficiency with the pharmacokinetic properties of copper ion, resulting in increasing cuproptosis-based anticancer effects. This review will summarize the intricate nexus between copper ion and carcinogenesis, examining the pivotal roles of copper homeostasis and its dysregulation in cancer progression and fatality. Furthermore, we will introduce the latest advances in cuproptosis-targeted nanomedicines for cancer treatment. Finally, the challenges in cuproptosis-based nanomedicines will be discussed for future development directions.
... Many researchers determined higher serum Cu and lower serum Zn levels in cervical cancer patients which have reflected the protective effects of higher serum Zn in cancer [38,39]. The increased serum Cu levels were linked and correlated with severe cancer condition, and they were even found resistant to chemotherapy than those cancer patients with lower serum Cu levels who were found responding positively to the same chemotherapy treatment which indicated that high serum Cu levels interfere with cancer cell killing mechanism of the cytotoxic drugs [83]. Even, Majumder et al. associated the higher serum Cu levels with stage and grade of tumor in cancer patients [83]. ...
... The increased serum Cu levels were linked and correlated with severe cancer condition, and they were even found resistant to chemotherapy than those cancer patients with lower serum Cu levels who were found responding positively to the same chemotherapy treatment which indicated that high serum Cu levels interfere with cancer cell killing mechanism of the cytotoxic drugs [83]. Even, Majumder et al. associated the higher serum Cu levels with stage and grade of tumor in cancer patients [83]. The Cu levels were revealed to be elevated in both tissues and blood serum of cancer patients than the healthy volunteers which indicated the occurrence of imbalanced Zn and Cu ratio in cancer patients [31,84]. ...
Various clinical manifestations associated with measurable abnormalities of Zn and Cu in serum and tissue were determined in Cancer-Patients (CP), and therefore, these two metals are drawing more and more attention presently than ever before. Cancer is a disease of uncontrolled-abnormal-cell-division with invasion-potential which was exhibited to occur due to dys-regulation/dys-homeostasis of fundamental-biological-pathways (FBP) including antioxidant-enzyme-defense-system, anti-inflammatory and immune-systems, and DNA-damage-repair-system in the human-body resulting in generation of chronic-oxidative-stress induced DNA-damage and gene-mutations, inflammation and compromised immune-system, tumor-induced increased angiogenesis, and inhibition of apoptosis processes. Zn and Cu were recognized to be the most crucial components of FBP and imbalance in Zn/Cu ratios in CP asserted to generate chronic toxicity in human body through various mechanisms including increased chronic oxidative stress linked compromised DNA integrity and gene mutations due to malfunctioning of DNA damage repair enzymes; increased angiogenesis process due to Zn- and Cu-binding proteins metallothionein and ceruloplasmin-induced enhanced expression of tumor growth factors; and elevation in inflammatory response which was further shown to down/upregulate gene expression of multiple Zn transporter proteins leading to dys-homeostasis of intracellular Zn concentrations, and it was determined to disturb the equilibrium between cell growth and division, proliferation, differentiation, and apoptosis processes which lead to cancer progression. Moreover, Zn was reported to affect matrix metalloproteinase activity and influence immune system cells to respond differently to different cytokines and enhance immune-suppressive effects accelerating the angiogenesis, invasion, and metastasis potential in cancer. Further, the most significant use of serum Cu/Zn ratio was recommended in clinical diagnosis, prognosis, tumor stage, patient survival, and cancer follow-up studies which need further investigations to elucidate and explore their roles in cancer physiology for clinical perspective.
... Transformed copper metabolism was found associated with tumorigenesis, dysregulated cell proliferation, induction of tumor microenvironment (TME), metastasis, angiogenesis, and cancer immunoediting [38][39][40]. Excessive amounts of intracellular copper have been detected in various cancers, including breast [41], prostate [42], colon [43], lung [44], brain [45], liver [46], head and neck [47], and endometrial [48] malignancies. Moreover, the accumulation of copper in tumor cells was also associated with the development of drug resistance [49,50], indicating the transformation of copper metabolism and signaling in malignant tissues. ...
Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.
Graphical Abstract
... Copper (Cu) serves as a cofactor for crucial enzymes in both animal cells and bacteria, and its presence is linked to the development, incidence, and prognosis of malignant tumors in humans [8]. In comparison with healthy individuals, 60% of breast cancer patients have elevated copper levels [9]. In hepatocellular carcinoma, severe disruption of mitochondrial homeostasis by DSF/Cu leads to increased iron storage, lipid peroxidation, and ultimately ferroptosis [10]. ...
Background
Glioma, a highly resistant and recurrent type of central nervous system tumor, poses a significant challenge in terms of effective drug treatments and its associated mortality rates. Despite the discovery of Ferredoxin 1 (FDX1) as a crucial participant in cuproptosis, an innovative mechanism of cellular demise, its precise implications for glioma prognosis and tumor immune infiltration remain inadequately elucidated.
Methods
To analyze pan-cancer data, we employed multiple public databases. Gene expression evaluation was performed using tissue microarray (TMA) and single-cell sequencing data. Furthermore, four different approaches were employed to assess the prognostic importance of FDX1 in glioma. We conducted the analysis of differential expression genes (DEGs) and Gene Set Enrichment Analysis (GSEA) to identify immune-related predictive signaling pathways. Somatic mutations were assessed using Tumor Mutation Burden (TMB) and waterfall plots. Immune cell infiltration was evaluated with five different algorithms. Furthermore, we performed in vitro investigations to evaluate the biological roles of FDX1 in glioma.
Results
Glioma samples exhibited upregulation of FDX1, which in turn predicted poor prognosis and was positively associated with unfavorable clinicopathological characteristics. Notably, the top four enriched signaling pathways were immune-related, and the discovery revealed a connection between the expression of FDX1 and the frequency of mutations or the TMB. The FDX1_high group exhibited heightened infiltration of immune cells, and there existed a direct association between the expression of FDX1 and the regulation of immune checkpoint. In vitro experiments demonstrated that FDX1 knockdown reduced proliferation, migration, invasion and transition from G2 to M phase in glioma cells.
Conclusion
In glioma, FDX1 demonstrated a positive association with the advancement of malignancy and changes in the infiltration of immune cells.
... Furthermore, copper has been demonstrated to be involved in tumor promotion and the development of drug resistance. A copper chelate was shown to be effective against drug resistance in previous studies that demonstrated copper's potential role in drug resistance by analyzing serum copper levels in mice with drug-sensitive and drug-resistant tumors, compared to healthy mice without tumors [105]. Moreover, approaches targeting nano-drug-based cell cuproptosis are being explored to enhance the efficiency of anticancer therapeutics [106]. ...
Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.
... Amongst the biometals, copper has emerged as an attractive target for designing nucleases having an anti-cancer activity [4][5][6][7][8][9][10]. Indeed, copper is an essential cofactor for tumor angiogenesis [11], while correlations exist between the copper status and both malignant progression [12,13] and response to therapy in some human cancers [14]. Furthermore, copper(II) is capable of favoring nucleophilic attack at the DNA phosphates, while copper(I) reacts with dioxygen, affording ROS that is potent for strand scission in vitro [15]. ...
Four ligands based on the 2-tert-butyl-4-X-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol unit are synthesized: X = CHO (HLCHO), putrescine-pyrene (HLpyr), putrescine (HLamine), and 2-tert-butyl-4-putrescine-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol (H2Lbis). Complexes 1, 2, 3, and 4 are formed upon chelation to copper(II). The crystal structure of complex 1 shows a square pyramidal copper center with a very weakly bound methoxypridine moiety in the apical position. The pKa of the phenol moiety is determined spectrophotometrically at 2.82–4.39. All the complexes show a metal-centered reduction in their CV at Epc,red = −0.45 to −0.5 V vs. SCE. The copper complexes are efficient nucleases towards the ϕX174 DNA plasmid in the presence of ascorbate. The corresponding IC50 value reaches 7 μM for 2, with a nuclease activity that follows the trend: 2 > 3 > 1. Strand scission is promoted by the hydroxyl radical. The cytotoxicity is evaluated on bladder cancer cell lines sensitive (RT112) or resistant to cisplatin (RT112 CP). The IC50 of the most active complexes (2 and 4) is 1.2 and 1.0 μM, respectively, for the RT112 CP line, which is much lower than cisplatin (23.8 μM).
... 7 Copper plays an important physiological and biochemical role in biological systems, such as the copper-dependent enzyme function, the occurrence, and development of tumors, cell proliferation, and drug resistance. [8][9][10][11] Many studies have found that copper is important in the drug resistance process in cells. Cuproptosis enhances the antitumor activity of multiple chemotherapeutic drugs and inhibits chemotherapy resistance. ...
Cuproptosis, a new type of copper‐induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib‐resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM‐regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.
... Kucharzewski et al. discovered that copper accumulates in the nuclear of breast cancer cells [49]. It has also been reported that increased serum copper in cancer patients is significantly associated with cancer grade and chemotherapy resistance [50]. So far, the metabolism of copper in ccRCC remains unclear. ...
Background
Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear.
Methods
We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC.
Results
The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells.
Conclusion
Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.
... Thus, high levels of Cu were reported within the tumoral cells of breast cancer [175]. It is likely that copper ions induce the formation of secondary tumours by activating some enzymes implicated in cell multiplication [176]. Moreover, increases in serum copper in cancer pathology were sometimes correlated with cancer stage. ...
... Moreover, increases in serum copper in cancer pathology were sometimes correlated with cancer stage. In addition, in the case of patients who are resistant to chemotherapy, increased levels of serum copper have been measured [176]. Data on different types of cancer on this subject are contradictory. ...
... These changes could be due to increased glycolysis and lactate formation. Furthermore, the Cu isotopic ratio could be used as an early diagnostic biomarker for cancer [176]. ...
Oncogenes are thought to play an important role in aberrant regulation of growth factors, which is believed to be an initiation event of carcinogenesis. However, recent genetic and pharmacological studies have shown that the Warburg effect (WE) is needed for tumour growth. It refers to extensively studied aerobic glycolysis over the past decade, although its impact on cancer remains unclear. Meanwhile, a large body of evidence has indicated that oxidative stress (OS) is connected with the occurrence and progression of various forms of cancer. Psychosocial factors (PSF), such as chronic depression, sadness, stressful life experiences, stress-prone personality, and emotional distress or poor quality of life affect the immune system and contribute to cancer outcomes. Here, we examine the relationship between WE, OS, PSF, metal ions, other carcinogens, and the development of different cancers from the viewpoint of physiological and biochemical mechanisms.
