Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas

Li, Yi; Fu, Shi-Yuan; Wei, Lihui; Wang, Fangyang; Wang, Nannan; Cao, Qi; Wang, Yating; Yang, Jingyu; Wu, Chunfu

doi:10.1016/j.canlet.2015.07.029

Cited by 77 publications

(63 citation statements)

References 50 publications

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“…DSF alone). These results substantiate previous in vitro 6 , 11 , 13 and in-vivo 6 – 9 , 13 , 16 studies indicating that DSF is an efficient anti-cancer agent and that copper potentiates its activity. As DSF’s reactive metabolite DTC forms complexes with metals, particularly copper, 17 we argued that a DTC-copper complex (CuET) forms in vivo ( Extended Data Fig.1d ), providing the ultimate anti-cancer metabolite.…”

Section: Anti-tumour Activity Of Dtc-copper Complex: Cuetsupporting

confidence: 91%

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Škrott

Mistrík

Andersen

et al. 2017

Nature

594

627

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Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to such unmet need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (Antabuse), an old alcohol-aversion drug effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify ditiocarb-copper complex as the metabolite of disulfiram responsible for anticancer effects, and provide methods to detect its preferential accumulation in tumours and candidate biomarkers for impact in cells and tissues. Finally, our functional and biophysical analyses reveal the long-sought molecular target of disulfiram’s tumour suppressing effects as NPL4, an adapter of p97/VCP segregase essential for protein turnover involved in multiple regulatory and stress-response cellular pathways.

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Section: Anti-tumour Activity Of Dtc-copper Complex: Cuetsupporting

confidence: 91%

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Škrott

Mistrík

Andersen

et al. 2017

Nature

594

627

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“…TTM and TEPA are not able to cross cell membrane and belong to the metal binding compounds that "sequesters" the metal ion outside the cell, thus rendering it biologically unavailable. Metal ionophores are metal ligands that diffuse from the extracellular space to the intracellular space and back to the extracellular space, they may also remain in the plasma membrane, increase intracellular metal content and kill cancer cells through different mechanisms [72][73][74][75].…”

Section: Vegf73-101 But Not Vegf84-101 Induces Apoptosis In Huvecmentioning

confidence: 99%

The Inorganic Perspective of VEGF: Interactions of Cu2+ with Peptides Encompassing a Recognition Domain of the VEGF Receptor

Grasso

Santoro

Magrı̀

et al. 2016

Journal of Inorganic Biochemistry

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“…Disulfiram is currently prescribed in the USA as a treatment for chronic alcoholism due to its inhibition of acetaldehyde dehydrogenase [ 11 ]. Surprisingly, Disulfiram was also identified as a top hit in HTS assays against prostate and breast cancer cell lines [ 12 , 13 ], and many anti-cancer activities in various cancer types have been described, such as proteasome inhibition [ 14 , 15 , 16 , 17 ]. Additionally, the proteasome inhibitor Bortezomib is also a potent cytotoxic for hM1- 2D and hM1-CAF, and does not provide selective effect on the cancer cells.…”

Section: Clinical Backgroundmentioning

confidence: 99%

Dynamic changes during the treatment of pancreatic cancer

et al. 2018

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This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient’s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment.

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Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas

Cited by 77 publications

References 50 publications

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

The Inorganic Perspective of VEGF: Interactions of Cu2+ with Peptides Encompassing a Recognition Domain of the VEGF Receptor

Dynamic changes during the treatment of pancreatic cancer

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