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disulfiram copper

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https://www.readbyqxmd.com/read/29665144/disulfiram-copper-targets-stem-cell-like-aldh-population-of-multiple-myeloma-by-inhibition-of-aldh1a1-and-hedgehog-pathway
#1
Na Jin, Xiaojian Zhu, Fanjun Cheng, Liling Zhang
Multiple myeloma stem cells (MMSCs) have been considered as the major cause resulting in relapse. Eradicating MMSCs may be an effective strategy to improve the outcome of multiple myeloma (MM). Increased activity of aldehyde dehydrogenase (ALDH) has been found in MMSCs, but whether inhibiting ALDH activity can eliminate MMSCs remains unknown. Disulfiram (DS) has been reported as an inhibitor of ALDH, and increasing studies showed it has anti-cancer effects in a copper (Cu)-dependent manner. In this study, we isolated ALDH+ cells of MM by Aldefluor assay and demonstrated they possessed tumorigenesis capacities in vitro and in vivo...
April 17, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29547841/suppressing-autophagy-enhances-disulfiram-copper-induced-apoptosis-in-non-small-cell-lung-cancer
#2
Xi Wu, Xue Xue, Lihui Wang, Wenjing Wang, Jian Han, Xiaoxue Sun, Haotian Zhang, Yueyang Liu, Xiaohang Che, Jingyu Yang, Chunfu Wu
Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells...
March 13, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29374809/final-results-of-a-phase-i-dose-escalation-dose-expansion-study-of-adding-disulfiram-with-or-without-copper-to-adjuvant-temozolomide-for-newly-diagnosed-glioblastoma
#3
Jiayi Huang, Jian L Campian, Amit D Gujar, Christina Tsien, George Ansstas, David D Tran, Todd A DeWees, A Craig Lockhart, Albert H Kim
Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper...
January 27, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29374195/restrained-management-of-copper-level-enhances-the-antineoplastic-activity-of-imatinib-in-vitro-and-in-vivo
#4
Iftekhar Hassan, Azmat Ali Khan, Shazia Aman, Wajhul Qamar, Hossam Ebaid, Jameel Al-Tamimi, Ibrahim M Alhazza, Ahmed M Rady
The present study was designed to investigate if elevated copper level can be targeted to enhance the efficacy of a significant anticancer drug, imatinib (ITB). The antineoplastic activity of this drug was assessed in the HepG2, HEK-293, MCF-7 and MDA-MD-231 cells targeting elevated copper level as their common drug target. The cell lines were treated with the different doses of copper chloride (Cu II) and disulfiram (DSF) alone as well as in their combinations with the drug for 24 h in standard culture medium and conditions...
January 26, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29274360/disulfiram-with-or-without-metformin-inhibits-oesophageal-squamous-cell-carcinoma-in-vivo
#5
Rupal Jivan, Jade Peres, Leonard Howard Damelin, Reubina Wadee, Robin Bruce Veale, Sharon Prince, Demetra Mavri-Damelin
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...
March 28, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29247315/development-of-a-copper-clioquinol-formulation-suitable-for-intravenous-use
#6
Moe Wehbe, Armaan K Malhotra, Malathi Anantha, Cody Lo, Wieslawa H Dragowska, Nancy Dos Santos, Marcel B Bally
Clioquinol (CQ) is an FDA-approved topical antifungal agent known to kill cancer cells. This facilitated the initiation of clinical trials in patients with refractory hematologic malignancies. These repurposing efforts were not successful; this was likely due to low intracellular levels of the drug owing to poor absorption and rapid metabolism upon oral administration. CQ forms a sparingly soluble copper complex (Cu(CQ)2 ) that exhibits enhanced anticancer activity in some cell lines. We have utilized a novel method to synthesize Cu(CQ)2 inside liposomes, an approach that maintains the complex suspended in solution and in a format suitable for intravenous administration...
February 2018: Drug Delivery and Translational Research
https://www.readbyqxmd.com/read/29211715/alcohol-abuse-drug-disulfiram-targets-cancer-via-p97-segregase-adaptor-npl4
#7
Zdenek Skrott, Martin Mistrik, Klaus Kaae Andersen, Søren Friis, Dusana Majera, Jan Gursky, Tomas Ozdian, Jirina Bartkova, Zsofia Turi, Pavel Moudry, Marianne Kraus, Martina Michalova, Jana Vaclavkova, Petr Dzubak, Ivo Vrobel, Pavla Pouckova, Jindrich Sedlacek, Andrea Miklovicova, Anne Kutt, Jing Li, Jana Mattova, Christoph Driessen, Q Ping Dou, Jørgen Olsen, Marian Hajduch, Boris Cvek, Raymond J Deshaies, Jiri Bartek
Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be 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...
December 14, 2017: Nature
https://www.readbyqxmd.com/read/29155365/targeting-aldh2-with-disulfiram-copper-reverses-the-resistance-of-cancer-cells-to-microtubule-inhibitors
#8
Nan-Nan Wang, Li-Hui Wang, Yi Li, Shi-Yuan Fu, Xue Xue, Li-Na Jia, Xiang-Zhong Yuan, Ya-Ting Wang, Xing Tang, Jing-Yu Yang, Chun-Fu Wu
Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone...
January 1, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29148232/disulfiram-combined-with-copper-inhibits-metastasis-and-epithelial-mesenchymal-transition-in-hepatocellular-carcinoma-through-the-nf-%C3%AE%C2%BAb-and-tgf-%C3%AE-pathways
#9
Yi Li, Li-Hui Wang, Hao-Tian Zhang, Ya-Ting Wang, Shuai Liu, Wen-Long Zhou, Xiang-Zhong Yuan, Tian-Yang Li, Chun-Fu Wu, Jing-Yu Yang
Late-stage hepatocellular carcinoma (HCC) usually has a low survival rate because of the high risk of metastases and the lack of an effective cure. Disulfiram (DSF) has copper (Cu)-dependent anticancer properties in vitro and in vivo. The present work aims to explore the anti-metastasis effects and molecular mechanisms of DSF/Cu on HCC cells both in vitro and in vivo. The results showed that DSF inhibited the proliferation, migration and invasion of HCC cells. Cu improved the anti-metastatic activity of DSF, while Cu alone had no effect...
January 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29135106/evidence-for-the-efficacy-of-disulfiram-and-copper-combination-in-glioblastoma-multiforme-a-propos-of-a-case
#10
Petros N Karamanakos, Dimitrios T Trafalis, Dionysios J Papachristou, Eleftheria S Panteli, Maria Papavasilopoulou, Andreas Karatzas, Dimitrios Kardamakis, Georgios Nasioulas, Marios Marselos
Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates...
September 2017: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/29065820/recent-advances-in-antabuse-disulfiram-the-importance-of-its-metal-binding-ability-to-its-anticancer-activity
#11
Maricela Viola-Rhenals, Kush Rohit Patel, Laura Jaimes-Santamaria, Guojun Wu, Jinbao Liu, Q Ping Dou
Disulfiram (DSF, also called tetraethylthiuram disulphide), a disulfide derivative of N,N-diethyldithiocarbamate (DEDTC), is an antialcoholism drug that is currently being repurposed as a promising anticancer drug. DSF has been investigated in many studies, including in vitro, in vivo, preclinical and clinical. Various mechanisms have been proposed to be responsible for the cytotoxic effect of DSF on cancer cells. DSF is a pro-drug which is converted to its metabolite DEDTC in human body. A complex of DEDTC with a metal ion [usually Cu(II) or Zn(II)] could be responsible for the anticancer activity of DSF in breast, prostate, glioblastoma, lung, melanoma, cervical, colorectal cancers as well as myeloma and leukemia...
October 23, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29029481/cell-cycle-specific-radiosensitisation-by-the-disulfiram-and-copper-complex
#12
Mathias Tesson, Giorgio Anselmi, Caitlin Bell, Robert Mairs
The disulfiram and copper complex (DSF:Cu) has emerged as a potent radiosensitising anti-cancer agent. The ability of copper to stabilise DSF in a planar conformation and to inhibit DNA replication enzymes stimulated our investigation of the effect of DSF:Cu on cell cycle regulation. Flow cytometry and immunoblotting were used to assess the effect of DSF:Cu on cell cycle progression of the neuroblastoma cell line SK-N-BE(2c) and the glioma cell line UVW. Treatment with 0.1 and 0.3 μM DSF:Cu inhibited DNA synthesis in SK-N-BE(2c) and UVW cells, respectively...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28974447/synergistic-toxicity-of-epigallocatechin-3-gallate-and-diethyldithiocarbamate-a-lethal-encounter-involving-redox-active-copper
#13
Ke Zhang, Ruixia Dong, Kang Sun, Xiaoxiao Wang, Jiajia Wang, Chung S Yang, Jinsong Zhang
Dithiocarbamates (DTC) are widely used in agricultural, industrial and therapeutic domains. There are ample opportunities for human exposure to DTC. Green tea extracts, with epigallocatechin-3-gallate (EGCG) being the most abundant constituent, have been used as dietary supplements for body weight reduction. Our hypothesis is that DTC can act as a copper ionophore to increase hepatic levels of redox-active copper which promotes EGCG auto-oxidation to produce oxidative stress and toxicity. The results of the present study in a mouse model is consistent with this hypothesis, showing that co-administration of EGCG and diethyldithiocarbamate - a metabolite of disulfiram (a drug for alcohol aversion therapy), both at tolerable levels, caused lethality...
September 30, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28864067/a-novel-chemoradiation-targeting-stem-and-nonstem-pancreatic-cancer-cells-by-repurposing-disulfiram
#14
Juan Cong, Yangyang Wang, Xiao Zhang, Nan Zhang, Ling Liu, Klara Soukup, Theodoros Michelakos, Theodore Hong, Albert DeLeo, Lei Cai, Francesco Sabbatino, Soldano Ferrone, Hang Lee, Vera Levina, Bryan Fuchs, Kenneth Tanabe, Keith Lillemoe, Cristina Ferrone, Xinhui Wang
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs...
November 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28709722/involvement-of-dopamine-beta-hydroxylase-in-the-neuroendocrine-immune-regulatory-network-of-white-shrimp-litopenaeus-vannamei
#15
Winton Cheng, Ya-Wen Ka, Chin-Chyuan Chang
In shrimp, the biosynthesis of catecholamines, including dopamine and norepinephrine, is required for physiological and immunological responses against stress. Dopamine beta-hydroxylase (DBH), a copper-containing monooxygenase enzyme that plays an important role in catecholamine synthesis of the neuroendocrine regulatory network, was identified in Litopenaeus vannamei. In the present study, the potential role of DBH in the immunocompetence of L. vannamei was further estimated by depleting DBH by pharmaceutical inhibition of disulfiram and a gene silencing technique of L...
July 11, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28615941/development-and-optimization-of-an-injectable-formulation-of-copper-diethyldithiocarbamate-an-active-anticancer-agent
#16
Mohamed Wehbe, Malathi Anantha, Minghan Shi, Ada Wai-Yin Leung, Wieslawa H Dragowska, Léon Sanche, Marcel B Bally
Copper diethyldithiocarbamate (Cu(DDC)2) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC)2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC)2 because of the inherent aqueous insolubility of the complex...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28528648/copper-and-antibiotics-discovery-modes-of-action-and-opportunities-for-medicinal-applications
#17
Alex G Dalecki, Cameron L Crawford, Frank Wolschendorf
Copper is a ubiquitous element in the environment as well as living organisms, with its redox capabilities and complexation potential making it indispensable for many cellular functions. However, these same properties can be highly detrimental to prokaryotes and eukaryotes when not properly controlled, damaging many biomolecules including DNA, lipids, and proteins. To restrict free copper concentrations, all bacteria have developed mechanisms of resistance, sequestering and effluxing labile copper to minimize its deleterious effects...
2017: Advances in Microbial Physiology
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#18
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28460441/inflammatory-breast-cancer-tumor-emboli-express-high-levels-of-anti-apoptotic-proteins-use-of-a-quantitative-high-content-and-high-throughput-3d-ibc-spheroid-assay-to-identify-targeting-strategies
#19
Jay Arora, Scott J Sauer, Michael Tarpley, Peter Vermeulen, Charlotte Rypens, Steven Van Laere, Kevin P Williams, Gayathri R Devi, Mark W Dewhirst
Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28373070/disulfiram-suppresses-cancer-stem-like-properties-and-stat3-signaling-in-triple-negative-breast-cancer-cells
#20
Yoon-Jae Kim, Ji Young Kim, Nahyun Lee, Eunhye Oh, Daeil Sung, Tae-Min Cho, Jae Hong Seo
In the presence of copper (Cu), disulfiram (DSF) suppresses properties associated with cancer stem cells (CSCs) in breast cancer, but the mechanism of action is poorly understood. In the present study, we observed that DSF/Cu treatment induced apoptosis, mediated by caspase-3 activation in triple-negative breast cancer (TNBC) cells. DSF/Cu treatment also specifically targeted CSC-like cell populations, marked by the inhibition of ALDH1 activity, the suppression of CD44+/CD24-and CD49f+/CD24 + subpopulations, and the subsequent impairment of mammosphere formation...
May 13, 2017: Biochemical and Biophysical Research Communications
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