Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders

Gohil, Vishal M.

doi:10.1080/13543784.2021.1840550

Cited by 35 publications

(15 citation statements)

References 24 publications

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“…Elesclomol binds to copper Cu ++ and deliver it into mitochondria, where it is released as Cu + that can react with molecular oxygen generating ROS which, when produced in excess, can cause unmitigated oxidative stress and apoptotic death of cancer cells [ 44 , 53 ]. Apoptosis also appears to be partly related with the ability of elesclomol and copper to inhibit the relaxation phase of topoisomerase I [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

Buccarelli

D’Alessandris

Matarrese

et al. 2021

J Exp Clin Cancer Res

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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.

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Section: Discussionmentioning

confidence: 99%

Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

Buccarelli

D’Alessandris

Matarrese

et al. 2021

J Exp Clin Cancer Res

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“…This also strongly hints at the relationship between cancer sensitivity to elesclomol and cellular metabolism. In the last two years, there has been renewed interest in elesclomol [ 14 ], whose specific transport function of copper ions to cellular mitochondria suggests its potential therapeutic for rare diseases of copper deficiency, such as the Menkes disease [ 15 ]. Here, we propose that the prospect of elesclomol in cancer metabolic therapy deserves special attention.…”

Section: Introductionmentioning

confidence: 99%

Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy

Zheng

Zhou

et al. 2022

J Exp Clin Cancer Res

150

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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.

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“…There is a dire need for the identification, characterization, and optimization of Cu transporting drugs because currently, no effective therapy exists for Cu deficiency disorders. Our recent studies have highlighted the potential of ES, an investigational cancer drug, as a therapeutic agent for disorders of Cu deficiency ( 17 , 18 , 19 ). In order to translate these promising preclinical studies into repurposing ES for the treatment of Cu deficiency disorders, it is critical to determine its specificity, toxicity, and impact on the overall cellular metallome.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we showed that elesclomol (ES), a Cu-binding investigational oncology drug, can traverse through cellular membranes and make Cu bioavailable to mitochondrial cytochrome c oxidase and rescue Cu-deficient phenotypes in yeast, zebrafish, and murine models ( 17 , 18 ). These exciting findings have raised the possibility of repurposing this cancer drug for the treatment of Cu deficiency disorders ( 19 ). ES is a bis (thiohydrazide) amide compound that was originally developed as an anticancer drug.…”

mentioning

confidence: 99%

Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery

Garza

Zulkifli

Gohil

2022

Journal of Biological Chemistry

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Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders

Cited by 35 publications

References 24 publications

Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy

Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery

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