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  1. Article ; Online: Disulfiram with or without metformin inhibits oesophageal squamous cell carcinoma in vivo.

    Jivan, Rupal / Peres, Jade / Damelin, Leonard Howard / Wadee, Reubina / Veale, Robin Bruce / Prince, Sharon / Mavri-Damelin, Demetra

    Cancer letters

    2017  Volume 417, Page(s) 1–10

    Abstract: Oesophageal squamous cell carcinoma (OSCC) is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies. Drug repurposing is one attractive approach for cancer therapy. ... ...

    Abstract Oesophageal squamous cell carcinoma (OSCC) is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies. Drug repurposing is one attractive approach for cancer therapy. Disulfiram (DSF), used to treat alcoholism, inhibits cancer growth and we previously found that DSF perturbs protein degradation/turnover pathways in vitro. This was enhanced by combining DSF with the anti-diabetic drug metformin (Met). Here, we investigated DSF with/without Met, against OSCC in vivo. Nude mice injected subcutaneously with the human OSCC cell line WHCO1, were treated with 30 mg/kg or 50 mg/kg DSF three times per week and with/without Met, for 21 days. DSF and DSF/Met-treated animals had significantly smaller tumours compared to untreated, vehicle and positive control cisplatin-treated groups. This effect for DSF was independent of copper, with no significant accumulation of copper in tumours, together with maintained proteasome activity. However, increases in total ubiquitinated proteins, LC3B-II, LAMP1 and p62 in DSF and DSF/Met groups, indicate that autophagy is inhibited. These findings show that DSF and DSF/Met significantly impede OSCC tumour growth in vivo and offer prospective alternative chemotherapy approaches for OSCC.
    MeSH term(s) Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Autophagy/drug effects ; Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Disulfiram/administration & dosage ; Esophageal Neoplasms/drug therapy ; Esophageal Neoplasms/pathology ; Humans ; Metformin/administration & dosage ; Mice, Nude ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Metformin (9100L32L2N) ; Disulfiram (TR3MLJ1UAI)
    Language English
    Publishing date 2017-12-20
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2017.12.026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Metformin induces an intracellular reductive state that protects oesophageal squamous cell carcinoma cells against cisplatin but not copper-bis(thiosemicarbazones).

    Damelin, Leonard Howard / Jivan, Rupal / Veale, Robin Bruce / Rousseau, Amanda Louise / Mavri-Damelin, Demetra

    BMC cancer

    2014  Volume 14, Page(s) 314

    Abstract: Background: Oesophageal squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a poor survival rate. One of the most commonly used chemotherapeutic drugs, cisplatin, displays varied and often poor efficacy in vivo. Therefore, alternative, ... ...

    Abstract Background: Oesophageal squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a poor survival rate. One of the most commonly used chemotherapeutic drugs, cisplatin, displays varied and often poor efficacy in vivo. Therefore, alternative, cost-effective and more efficacious treatments are required. Metformin has been previously shown to reduce proliferative rates in various carcinoma cell lines. We report for the first time, the effect of metformin on OSCC cell proliferation and show that it antagonises cisplatin-induced but not copper-bis(thiosemicarbazone)-induced cytotoxicity in OSCC cells.
    Methods: Cell proliferation and stage of the cell cycle were quantified by trypan blue counts and flow cytometry, respectively. All cytotoxicity measurements were made using the tetrazolium based MTT assay. Metabolic alterations to cells were determined as follows: glycolysis via a lactate dehydrogenase assay, reducing equivalents by MTT reduction and reduced intracellular thiols by monobromobimane-thiol fluorescence, and glutathione depletion using buthionine sulfoximine. Inductively coupled plasma mass spectrometry was used to quantify cisplatin-DNA adduct formation.
    Results: Metformin was found to reduce cell proliferation significantly in all OSCC cell lines, with an accumulation of cells in G0/G1 phase of the cell cycle. However, metformin significantly protected OSCC cells against cisplatin toxicity. Our results indicate that a major mechanism of metformin-induced cisplatin resistance results from a significant increase in glycolysis, intracellular NAD(P)H levels with a concomitant increase in reduced intracellular thiols, leading to decreased cisplatin-DNA adduct formation. The glutathione synthesis inhibitor buthionine sulfoximine significantly ablated the protective effect of metformin. We subsequently show that the copper-bis(thiosemicarbazones), Cu-ATSM and Cu-GTSM, which are trapped in cells under reducing conditions, cause significant OSCC cytotoxicity, both alone and in combination with metformin.
    Conclusions: This is the first study showing that metformin can be used to decrease cell proliferation in OSCC cells. However, metformin protects against cisplatin cytotoxicity by inducing a reducing intracellular environment leading to lower cisplatin-DNA adduct formation. As such, we advise that caution be used when administering cisplatin to diabetic patients treated with metformin. Furthermore, we propose a novel combination therapy approach for OSCC that utilises metformin with metformin-compatible cytotoxic agents, such as the copper-bis(thiosemicarbazones), Cu-ATSM and Cu-GTSM.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cisplatin/pharmacology ; Coordination Complexes/pharmacology ; DNA Adducts/metabolism ; Dose-Response Relationship, Drug ; Esophageal Neoplasms/metabolism ; Esophageal Neoplasms/pathology ; Glutathione/metabolism ; Glycolysis/drug effects ; Humans ; L-Lactate Dehydrogenase/metabolism ; Metformin/pharmacology ; Organometallic Compounds/pharmacology ; Oxidation-Reduction ; Sulfhydryl Compounds/metabolism ; Thiosemicarbazones/pharmacology
    Chemical Substances Antineoplastic Agents ; Coordination Complexes ; DNA Adducts ; Organometallic Compounds ; Sulfhydryl Compounds ; Thiosemicarbazones ; copper (II) diacetyl-di(N(4)-methylthiosemicarbazone) ; glyoxal-bis(4-methylthiosemicarbazonato)copper(II) ; Metformin (9100L32L2N) ; L-Lactate Dehydrogenase (EC 1.1.1.27) ; Glutathione (GAN16C9B8O) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2014-05-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1471-2407
    ISSN (online) 1471-2407
    DOI 10.1186/1471-2407-14-314
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Disulfiram/copper-disulfiram Damages Multiple Protein Degradation and Turnover Pathways and Cytotoxicity is Enhanced by Metformin in Oesophageal Squamous Cell Carcinoma Cell Lines.

    Jivan, Rupal / Damelin, Leonard Howard / Birkhead, Monica / Rousseau, Amanda Louise / Veale, Robin Bruce / Mavri-Damelin, Demetra

    Journal of cellular biochemistry

    2015  Volume 116, Issue 10, Page(s) 2334–2343

    Abstract: Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol-reactive and readily complex copper. More recently DSF and copper-DSF (Cu-DSF) have been found to ... ...

    Abstract Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol-reactive and readily complex copper. More recently DSF and copper-DSF (Cu-DSF) have been found to exhibit potent anticancer activity. We have previously shown that the anti-diabetic drug metformin is anti-proliferative and induces an intracellular reducing environment in oesophageal squamous cell carcinoma (OSCC) cell lines. Based on these observations, we investigated the effects of Cu-DSF and DSF, with and without metformin, in this present study. We found that Cu-DSF and DSF caused considerable cytotoxicity across a panel of OSCC cells, and metformin significantly enhanced the effects of DSF. Elevated copper transport contributes to DSF and metformin-DSF-induced cytotoxicity since the cell-impermeable copper chelator, bathocuproinedisulfonic acid, partially reversed the cytotoxic effects of these drugs, and interestingly, metformin-treated OSCC cells contained higher intracellular copper levels. Furthermore, DSF may target cancer cells preferentially due to their high dependence on protein degradation/turnover pathways, and we found that metformin further enhances the role of DSF as a proteasome inhibitor. We hypothesized that the lysosome could be an additional, novel, target of DSF. Indeed, this acid-labile compound decreased lysosomal acidification, and DSF-metformin co-treatment interfered with the progression of autophagy in these cells. In summary, this is the first such report identifying the lysosome as a target of DSF and based on the considerable cytotoxic effects of DSF either alone or in the presence of metformin, in vitro, and we propose these as novel potential chemotherapeutic approaches for OSCC.
    MeSH term(s) Carcinoma, Squamous Cell/drug therapy ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Copper/administration & dosage ; Disulfiram/administration & dosage ; Drug Synergism ; Esophageal Neoplasms/drug therapy ; Esophageal Neoplasms/pathology ; Esophageal Squamous Cell Carcinoma ; Humans ; Metformin/administration & dosage ; Proteasome Endopeptidase Complex/administration & dosage ; Proteolysis/drug effects
    Chemical Substances Copper (789U1901C5) ; Metformin (9100L32L2N) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Disulfiram (TR3MLJ1UAI)
    Language English
    Publishing date 2015-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.25184
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1114: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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