RETRACTED: Disulfiram Chelated With Copper Inhibits the Growth of Gastric Cancer Cells by Modulating Stress Response and Wnt/β-catenin Signaling

Chai, Xudong; Wan, Run; Zhang, Hong; Zhou, Cong; Lin, Xiang; Paul, Maswikiti Ewetse; Li, Yumin

doi:10.3389/fonc.2020.595718

Cited by 25 publications

(9 citation statements)

References 59 publications

(76 reference statements)

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“…A much-debated question is whether copper up or down regulated the level of C-myc. The previous study has found that increasing intracellular copper ion concentration through disulfiram(DSF) leads to a decrease in the expression of β-catenin and C-myc, two important molecules of the Wnt pathway, thereby inhibiting tumor growth [ 66 ]. However, a more recent research argued that the Copper elevates C-myc stability by promoting phosphorylation at its threonine 58 and serine 62 sites [ 67 ].…”

Section: Introductionmentioning

confidence: 99%

Cuproptosis: mechanisms and links with cancers

et al. 2023

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Cuproptosis was a copper-dependent and unique kind of cell death that was separate from existing other forms of cell death. The last decade has witnessed a considerable increase in investigations of programmed cell death, and whether copper induced cell death was an independent form of cell death has long been argued until mechanism of cuproptosis has been revealed. After that, increasing number of researchers attempted to identify the relationship between cuproptosis and the process of cancer. Thus, in this review, we systematically detailed the systemic and cellular metabolic processes of copper and the copper-related tumor signaling pathways. Moreover, we not only focus on the discovery process of cuproptosis and its mechanism, but also outline the association between cuproptosis and cancers. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosis-inducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers.

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Section: Introductionmentioning

confidence: 99%

Cuproptosis: mechanisms and links with cancers

et al. 2023

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“…The antitumor efficacy of DSF depends on the presence or absence of Cu ions, as demonstrated in several studies [ 10 , 12 , 21 , 26 , 29 , 32 , 33 ]. Some studies showed that DSF metabolites chelate Cu ions to form CUET in vivo and in vitro [ 14 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Studies indicated that DSF/Cu inhibits the growth of GC cells by modulating the stress response and Wnt/β-catenin/NF-κβ signaling [ 26 , 27 ]. Consistent with our study, these studies found that DSF/Cu induced anti-GC activity through the joint action of several pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence suggest the anticancer activity of DSF with several mechanisms focused on elevating intracellular reactive oxygen species (ROS) levels [ 8–10 ], reducing acetaldehyde dehydrogenase (ALDH) expression to weaken the stemness of cancer cells [ 8 , 11–13 ], and disturbing the ubiquitin-proteasome system [ 14–16 ], or causing DNA damage [ 17 , 18 ]. These antitumor effects were reported in many preclinical studies and recently in several types of human cancer (prostate [ 19 ], liver [ 20 , 21 ], and ovarian cancer [ 8 ], glioblastoma [ 17 , 22 ], lung [ 23 ], breast [ 24 ], pancreatic [ 24 ], acute myeloid leukemia [ 9 ], melanoma [ 25 ], and GC [ 26 , 27 ])…”

Section: Introductionmentioning

confidence: 91%

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Disulfiram/Copper induces antitumor activity against gastric cancer via the ROS/MAPK and NPL4 pathways

Liu

Guan²,

Wang

et al. 2022

Bioengineered

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Disulfiram (DSF) is an anti-alcoholism medication with superior antitumor activity and clinical safety; its antitumor mechanisms in gastric cancer (GC) have not been fully explored. In the present work, low nontoxic concentrations of copper (Cu) ions substantially enhanced DSF’s antitumor activity, inhibiting the proliferation and growth of GC cell lines. DSF/Cu elevated the generation of reactive oxygen species (ROS), and apoptosis was induced in an ROS-dependent manner. This process might involve primary inhibition GC by DSF/Cu through induction of apoptosis via the ROS/mitogen-activated protein kinase pathway. Disordering transportation of ubiquitinated protein may also fuel the process. In summary, we found that DSF exerts antitumor effects on GC. DSF/Cu should be considered as adjunctive therapy for GC.

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“…In addition, disulfiram (DSF) was an approved drug for anti-alcoholism medication and accumulating evidence suggested DSF, in combination with copper, showed excellent antitumor activity in multiple cancers, including GC ( 66 ). For example, DSF/Cu complex exhibited antitumor activity against GC cells via modulating the stress response, glycolysis, S6K1, c-Myc and Wnt/β-catenin signaling ( 67 , 68 ). DSF/Cu also induced apoptosis through reactive oxygen species (ROS)/mitogen-activated protein kinase pathway ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer

et al. 2022

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IntroductionCuproptosis is a novel identified regulated cell death (RCD), which is correlated with the development, treatment response and prognosis of cancer. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of gastric cancer (GC) remains unknown.MethodsTranscriptome profiling, somatic mutation, somatic copy number alteration and clinical data of GC samples were downloaded from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database to describe the alterations of CRGs from genetic and transcriptional fields. Differential, survival and univariate cox regression analyses of CRGs were carried out to investigate the role of CRGs in GC. Cuproptosis molecular subtypes were identified by using consensus unsupervised clustering analysis based on the expression profiles of CRGs, and further analyzed by GO and KEGG gene set variation analyses (GSVA). Genes in distinct molecular subtypes were also analyzed by GO and KEGG gene enrichment analyses (GSEA). Differentially expressed genes (DEGs) were screened out from distinct molecular subtypes and further analyzed by GO enrichment analysis and univariate cox regression analysis. Consensus clustering analysis of prognostic DEGs was performed to identify genomic subtypes. Next, patients were randomly categorized into the training and testing group at a ratio of 1:1. CRG Risk scoring system was constructed through logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis, univariate and multivariate cox analyses in the training group and validated in the testing and combined groups. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of key Risk scoring genes. Sensitivity and specificity of Risk scoring system were examined by using receiver operating characteristic (ROC) curves. pRRophetic package in R was used to investigate the therapeutic effects of drugs in high- and low- risk score group. Finally, the nomogram scoring system was developed to predict patients’ survival through incorporating the clinicopathological features and CRG Risk score.ResultsMost CRGs were up-regulated in tumor tissues and showed a relatively high mutation frequency. Survival and univariate cox regression analysis revealed that LIAS and FDX1 were significantly associated with GC patients’ survival. After consensus unsupervised clustering analysis, GC patients were classified into two cuproptosis molecular subtypes, which were significantly associated with clinical features (gender, age, grade and TNM stage), prognosis, metabolic related pathways and immune cell infiltration in TME of GC. GO enrichment analyses of 84 DEGs, obtained from distinct molecular subtypes, revealed that DEGs primarily enriched in the regulation of metabolism and intracellular/extracellular structure in GC. Univariate cox regression analysis of 84 DEGs further screened out 32 prognostic DEGs. According to the expression profiles of 32 prognostic DEGs, patients were re-classified into two gene subtypes, which were significantly associated with patients’ age, grade, T and N stage, and survival of patients. Nest, the Risk score system was constructed with moderate sensitivity and specificity. A high CRG Risk score, characterized by decreased microsatellite instability-high (MSI-H), tumor mutation burden (TMB) and cancer stem cell (CSC) index, and high stromal and immune score in TME, indicated poor survival. Four of five key Risk scoring genes expression were dysregulated in tumor compared with normal samples. Moreover, CRG Risk score was greatly related with sensitivity of multiple drugs. Finally, we established a highly accurate nomogram for promoting the clinical applicability of the CRG Risk scoring system.DiscussionOur comprehensive analysis of CRGs in GC demonstrated their potential roles in TME, clinicopathological features, and prognosis. These findings may improve our understanding of CRGs in GC and provide new perceptions for doctors to predict prognosis and develop more effective and personalized therapy strategies.

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RETRACTED: Disulfiram Chelated With Copper Inhibits the Growth of Gastric Cancer Cells by Modulating Stress Response and Wnt/β-catenin Signaling

Cited by 25 publications

References 59 publications

Cuproptosis: mechanisms and links with cancers

Cuproptosis: mechanisms and links with cancers

Disulfiram/Copper induces antitumor activity against gastric cancer via the ROS/MAPK and NPL4 pathways

Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer

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