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Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol’s anticancer activity is determined by the dependence of cancer on mitochondrial metabolism. The mitochondrial metabolism of cancer stem cells, cancer cells resistant to platinum drugs, proteasome inhibitors, molecularly targeted drugs, and cancer cells with inhibited glycolysis was significantly enhanced. Elesclomol exhibited tremendous toxicity to all three kinds of cells. Elesclomol's toxicity to cells is highly dependent on its transport of extracellular copper ions, a process involved in cuproptosis. The discovery of cuproptosis has perfected the specific cancer suppressor mechanism of elesclomol. For some time, elesclomol failed to yield favorable results in oncology clinical trials, but its safety in clinical application was confirmed. Research progress on the relationship between elesclomol, mitochondrial metabolism and cuproptosis provides a possibility to explore the reapplication of elesclomol in the clinic. New clinical trials should selectively target cancer types with high mitochondrial metabolism and attempt to combine elesclomol with platinum, proteasome inhibitors, molecularly targeted drugs, or glycolysis inhibitors. Herein, the particular anticancer mechanism of elesclomol and its relationship with mitochondrial metabolism and cuproptosis will be presented, which may shed light on the better application of elesclomol in clinical tumor treatment.

Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol‐mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper‐transporting ATPase 1 (ATP7A), which retards the proliferation of CRC cells. This property distinguishes it from several other copper chelators. Combinational treatment of elesclomol and copper leads to copper retention within mitochondria due to ATP7A loss, leading to reactive oxygen species accumulation, which in turn promotes the degradation of SLC7A11, thus further enhancing oxidative stress and consequent ferroptosis in CRC cells. This effect accounts for the robust antitumour activity of elesclomol against CRC, which can be reversed by the administration of antioxidants and ferroptosis inhibitors, as well as the overexpression of ATP7A. In summary, our findings indicate that elesclomol‐induced copper chelation inhibits CRC by targeting ATP7A and regulating ferroptosis. In this study, we describe the molecular mechanisms by which elesclomol‐mediated copper (Cu2+) overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol elevated Cu2+ levels in mitochondria and decreased the expression of the Cu2+ transporter ATP7A, leading to Cu2+ retention and the subsequent accumulation of reactive oxygen species. The process promoted the degradation of SLC7A11, which further enhanced oxidative stress and induced ferroptosis in CRC cells.

The induction of cuproptosis, a recently identified form of copper‐dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu2+) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis‐inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis‐mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor‐infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death‐1 (PD‐1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis‐mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy. A copper oxide (CuO)‐based and copper ionophore elesclomol (ES)‐loaded nanoplatform (denoted ES@CuO) is designed to trigger immunogenic cell death via cuproptosis. Meanwhile, combined therapy with ES@CuO nanoparticles and PD‐1 synergistically remodels the immunosuppressive tumor microenvironment to significantly inhibit the growth of murine melanoma.

Copper (Cu) is an essential element that is involved in a variety of biochemical processes. Both deficiency and accumulation of Cu are associated with various diseases; and a high amount of accumulated Cu in cells can be fatal. The production of reactive oxygen species (ROS), oxidative stress, and cuproptosis are among the proposed mechanisms of copper toxicity at high concentrations. Elesclomol (ELC) is a mitochondrion-targeting agent discovered for the treatment of solid tumors. In this review, we summarize the synthesis of this drug, its mechanisms of action, and the current status of its applications in the treatment of various diseases such as cancer, tuberculosis, SARS-CoV-2 infection, and other copper-associated disorders. We also provide some detailed information about future directions to improve its clinical performance.

Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.

Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half‐life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)‐responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES‐Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high‐level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+‐stimulated Fenton‐like reaction together with CA‐stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli‐dissociation of ECPCP, forming a positive feedback therapy loop against tumor self‐alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application. In this study, a self‐ampslifying ROS‐responsive nanoplatform (ECPCP) is developed, of which a polymer based on cinnamaldehyde and polyethylene glycol is fabricated to encapsulate elesclomol‐Cu compound. ECPCP successfully prolongs the systemic circulation of elesclomol and enhances its tumor accumulation, subsequently improving the dual antitumor mechanism of ES, cuproptosis, and immunotherapy, and provides a potential optimization for ES clinical application.

Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit ( GCLM ) and glutamate-cysteine ligase catalytic subunit ( GCLC ). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.

    Copper is essential in living organisms and crucial to various physiological processes. Normal physiological conditions are in a state of copper homeostasis to ensure normal biochemical and metabolic processes. Dysregulation of copper homeostasis has been associated with multiple diseases, especially cancer. Cuproptosis is a copper-dependent cell death mediated by excess copper or homeostasis dysregulation. Elesclomol is a common inducer of cuproptosis, carrying copper into the cell and producing excess copper. Cuproptosis modulates tumor proliferation-related signaling pathways and is closely associated with remodeling the tumor microenvironment. In gliomas, the role of cuproptosis and copper homeostasis needs to be better characterized. This study systematically analyzed cuproptosis-related genes (CRGs) and constructed a cuproptosis signature for gliomas. The signature closely links the subtypes and clinical features of glioma patients. The results showed a greater tendency toward dysregulation of copper homeostasis as the malignant grade of glioma patients increased. In addition, CRGs-signature effectively predicted the sensitivity of glioma cells to elesclomol and verified that elesclomol inhibited glioma mainly through inducing cellular cuproptosis. In summary, we found different copper homeostatic features in gliomas and verified the anticancer mechanism of elesclomol, which provides a theoretical basis for developing novel therapeutic strategies for gliomas.