Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy
Cancers · 3 authors, 2 centres
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This review summarizes the mechanisms of cuproptosis, a novel form of copper-induced cell death distinct from apoptosis, ferroptosis, and pyroptosis. It highlights the role of copper ionophores like elesclomol and disulfiram in triggering cell death via mitochondrial respiration and protein lipoylation, with potential applications in cancer therapy. The clinical significance lies in identifying cuproptosis as a target for treating cancers such as non-small cell lung cancer, colorectal cancer, prostate cancer, and uveal melanoma.
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**Background:** Copper is an essential trace element that must be tightly regulated to avoid toxicity. Cuproptosis is a recently identified form of programmed cell death driven by copper overload, distinct from apoptosis, ferroptosis, and pyroptosis. This review explores the mechanisms of cuproptosis, its role in health and disease, and its potential as a therapeutic target in cancer.
**Methods:** The authors conducted a narrative review of the literature, surveying studies on copper biochemistry, copper ionophores (elesclomol and disulfiram), mitochondrial respiration, protein lipoylation, and copper-related diseases (Wilson and Menkes diseases). They also reviewed preclinical and clinical studies on copper-based nanomaterials and copper-targeted therapies in various cancers.
**Key Results:** Cuproptosis is characterized by copper binding to lipoylated mitochondrial proteins, particularly DLAT, leading to proteotoxic stress and cell death. Cells dependent on mitochondrial respiration are 1000-fold more sensitive to copper ionophores than glycolytic cells. Key mediators include FDX1, which reduces Cu2+ to Cu+, and the lipoic acid pathway. Copper ionophores like elesclomol and disulfiram induce oxidative stress and inhibit proteasomes. In non-small cell lung cancer, a phase II trial combining disulfiram with cisplatin and vinorelbine improved survival (10 months vs. 7.1 months). In uveal melanoma, elesclomol suppressed cell viability and migration. Copper-based nanomaterials, such as GOx@[Cu(tz)], achieved 92.4% tumor inhibition in bladder cancer models. Elevated serum copper is associated with cancer staging in colorectal and breast cancers.
**Clinical Implications:** Cuproptosis offers a novel therapeutic avenue for cancers resistant to conventional cell death pathways. Copper ionophores and chelators are being explored in clinical trials, but challenges remain in identifying specific biomarkers and improving selectivity for cancer cells. Understanding the regulatory mechanisms of cuproptosis is essential for developing targeted therapies.