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Pharmaceuticals (Basel) 2022 Jun 13;15(6). Epub 2022 Jun 13.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.

One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Read More

Syst Rev 2022 06 2;11(1):109. Epub 2022 Jun 2.

Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, 730030, P.R. China.

Background And Objectives: Cancer morbidity and mortality rates remain high, and thus, at present, considerable efforts are focused on finding drugs with higher sensitivity against tumor cells and fewer side effects. Disulfiram (DSF), as an anti-alcoholic drug, kills the cancer cells by inducing apoptosis. Several preclinical and clinical studies have examined the potential of repurposing DSF as an anticancer treatment. Read More

Mol Cancer Ther 2022 May 17. Epub 2022 May 17.

University of Wolverhampton, Wolverhampton, United Kingdom.

Glioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NFκB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Read More

Angew Chem Int Ed Engl 2022 May 5:e202203500. Epub 2022 May 5.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

Selective activation of prodrugs is an important approach to reduce the side effects of disease treatment. We report a prodrug design concept for metal complexes, termed "metal-carrying prochelator", which can co-carry a metal ion and chelator within a single small-molecule compound and remain inert until it undergoes a specifically triggered intramolecular chelation to synthesize a bioactive metal complex in situ for targeted therapy. As a proof-of-concept, we designed a H O -responsive small-molecule prochelator, DPBD, based on the strong chelator diethyldithiocarbamate (DTC) and copper. Read More

Korean J Physiol Pharmacol 2022 May;26(3):157-164

College of Veterinary Medicine, Jeju National University, Jeju 63243, Korea.

Disulfiram (DSF) is an aldehyde dehydrogenase inhibitor. DSF has potent anti-cancer activity for solid and hematological malignancies. Although the effects on cancer cells have been proven, there have been few studies on DSF toxicity in bone marrow cells (BMs). Read More

Curr Oncol 2022 04 16;29(4):2808-2822. Epub 2022 Apr 16.

Department of Gynecology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer-related death. The high mortality and morbidity associated with EOC are mostly due to late diagnosis and chemotherapy drug resistance. Currently, the standard first-line chemotherapy regimen is systemic administration of platinum-based chemotherapy combined with a taxane. Read More

Biomaterials 2022 05 4;284:121513. Epub 2022 Apr 4.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People's Republic of China. Electronic address:

Disulfiram (DSF), an effective FDA-approved anti-alcoholism drug, shows potent antitumor activity by producing Cu(DTC), a chelate of its metabolite diethyldithiocarbamate (DTC) and copper. However, the rapid metabolism and unselective distribution of DSF and the insufficient endogenous copper severely restrict enough bioactive Cu(DTC) generation in tumor tissues to achieve satisfactory antitumor effect. Moreover, directly Cu(DTC) administration also suffers from serious systemic toxicity. Read More

J Colloid Interface Sci 2022 Jun 3;615:517-526. Epub 2022 Feb 3.

School of Chemical Engineering, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address:

Off-target toxicity remains a major limitation of current cancer therapy, necessitating an alternative precision approach to treat cancers. Herein, a tumor microenvironment (TME)-triggered anticancer strategy was developed by constructing an anti-alcoholism drug disulfiram (DSF)-loaded, Cu-doped zeolite imidazolate frameworks-8 (DSF-Cu/ZIF-8) nanoparticle followed by PEGylation (PEG-DSF-Cu/ZIF-8) to realize in situ generation of cytotoxic compounds specifically in TME. The PEG-DSF-Cu/ZIF-8 demonstrated excellent hydrolytic stability in normal physiological conditions, guaranteeing the minimized off-target release of disulfiram and Cu ions. Read More

Eur Rev Med Pharmacol Sci 2021 Dec;25(24):7806-7822

Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia.

Objective: Mitoxantrone (MTX)- induced cardiotoxicity is a clinical concern that is limiting its use. The aim of this paper, therefore, was to investigate the subchronic administration of MTX plus nonspecific/specific inhibitors of CYP450/2E1, to assess the extent of oxidative-induced injury by measuring levels of oxidative cardiac and injury biomarkers in mice and to evaluate the effects of CYP2E1 on caspase 3 activity and nuclear factor erythroid 2-related factor-2 (NRF-2).

Materials And Methods: Mice (n = 32) were divided into four treatment groups of eight: control, MTX, MTX + 4-methlypyrazole (4MP) and MTX + disulfiram (Disf). Read More

Langmuir 2022 01 31;38(1):584-592. Epub 2021 Dec 31.

State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Disulfiram (DSF) is a clinical antialcoholism drug that has been confirmed to show anticancer bioactivity after chelating with Cu. Therefore, how to co-deliver DSF and Cu to tumor tissues and generate a smart response to the tumor microenvironment (TME) are the focus of repurposing DSF for the effective treatment of cancer. Herein, we fabricated facilely a smart nanosystem by coating tannic acid (TA) and Cu network on DSF, denoted as [email protected], which responses well to TME and forms CuET complex in situ. Read More

Cells 2021 11 24;10(12). Epub 2021 Nov 24.

Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

Nephropathic cystinosis is a rare disease caused by mutations of the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. The disease is characterized by early-onset chronic kidney failure and progressive development of extra-renal complications related to cystine accumulation in all tissues. At the cellular level, several alterations have been demonstrated, including enhanced apoptosis, altered autophagy, defective intracellular trafficking, and cell oxidation, among others. Read More

Int J Pharm 2022 Jan 6;612:121351. Epub 2021 Dec 6.

National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu 610064, China. Electronic address:

Disulfiram (DSF) has a copper (II)-potentiated anticancer activity in various cancers. Synchronous delivery of DSF and cupric ions to tumor tissues is challenging but holds great potential in improving antitumor outcomes and promoting clinical translation. Herein, we reported a disulfiram prodrug (DQ)-loaded and glucose oxidase (GOD) conjugated copper (II)-based nanoscale metal-organic framework (MOF), MPDG, for tumor-specific, enhanced chemo-chemodynamic therapy. Read More

J Control Release 2022 01 29;341:351-363. Epub 2021 Nov 29.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address:

Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC), which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles ([email protected]) was established as a copper carrier to achieve synchronous but separate delivery of Cu and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC) generation for antitumor therapy. Read More

J Phys Chem Lett 2021 Nov 3;12(44):10880-10885. Epub 2021 Nov 3.

State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences, Changchun 130022, China.

Despite the fact that chemotherapy has been widely used in the clinical treatment of breast cancer, the toxicity of chemotherapeutics to normal tissues cannot be ignored due to the low specificity. Therefore, due to the non-negligible toxicity of chemotherapeutic agents to normal tissues, tumor microenvironment (TME)-responsive cancer therapy has attracted a great deal of attention. Here, we report a TME-responsive theranostic nanoagent [email protected]@[email protected] fabricated via a layer-by-layer synthesis method. Read More

Nanotoxicology 2021 11 16;15(9):1125-1150. Epub 2021 Oct 16.

Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Carbon nanotubes (CNTs) have been extensively investigated, and several studies have shown that multi-walled CNTs can trigger inflammation and fibrosis in animal models. However, while neutrophils are involved in inflammation, most studies have addressed macrophages. Here we explored the impact of three MWCNTs with varying morphology (i. Read More

Mol Oncol 2022 04 26;16(7):1541-1554. Epub 2021 Oct 26.

Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University, Olomouc, Czech Republic.

Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies, case reports, and small clinical trials; however, ongoing clinical trials of advanced-stage cancer patients encounter variable results. Here, we show that one reason for the inconsistent clinical effects of DSF may reflect interference by other drugs. Read More

Front Mol Biosci 2021 17;8:741316. Epub 2021 Sep 17.

Departments of Oncology, Pharmacology and Pathology, School of Medicine, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Read More

J Nanobiotechnology 2021 Sep 27;19(1):290. Epub 2021 Sep 27.

Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai, 200444, People's Republic of China.

Background: In comparison with traditional therapeutics, it is highly preferable to develop a combinatorial therapeutic modality for nanomedicine and photothermal hyperthermia to achieve safe, efficient, and localized delivery of chemotherapeutic drugs into tumor tissues and exert tumor-activated nanotherapy. Biocompatible organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) have shown high performance in molecular imaging and drug delivery as compared to other inorganic nanosystems. Disulfiram (DSF), an alcohol-abuse drug, can act as a chemotherapeutic agent according to its recently reported effectiveness for cancer chemotherapy, whose activity strongly depends on copper ions. Read More

Biomed Pharmacother 2021 Nov 15;143:112168. Epub 2021 Sep 15.

Department of Histology and Embryology, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia.

We investigated the anticancer effect of disulfiram and metformin combination on fibrosarcoma in hamsters. Hamsters of both sexes (~ 70 g) were randomly allocated to control and experimental groups (8 animals per group). In all 10 groups, 2 × 10 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' backs. Read More

Microbiol Spectr 2021 10 1;9(2):e0077821. Epub 2021 Sep 1.

Department of Immunobiology, University of Arizonagrid.134563.6, Tucson, Arizona, USA.

Transition metals are necessary cofactors and structural elements in living systems. Exposure to high concentrations of biologically important transition metals, such as zinc and copper, results in cell toxicity. At the infection site, the immune system deploys metal sorbent proteins (e. Read More

Acta Pharm Sin B 2021 Jul 24;11(7):2016-2030. Epub 2021 Jan 24.

School of Pharmacy, School of Pharmaceutical Sciences, Zhengzhou University; Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, China.

Although approved as an alcohol-abuse drug, disulfiram (DSF) exhibited potential anticancer activity when chelated with copper (Cu). However, the low level of intrinsic Cu, toxicity originated from exogenous Cu supplementation, and poor stability of DSF severely limited its application in cancer treatment. Herein, we proposed an DSF antitumor efficacy triggered system, taking advantages of Cu-based metal-organic framework (MOF). Read More

Neurooncol Adv 2021 Jan-Dec;3(1):vdab075. Epub 2021 Jun 24.

Department of Neurosurgery, Ulm University Hospital, Ulm, Germany.

Background: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide-version 3-(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. Read More

Int J Pharm 2021 Sep 8;607:120978. Epub 2021 Aug 8.

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China; Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address:

Disulfiram (DSF) is an effective copper (Cu)-dependent antitumor agent. In the present study, we explored use of transferrin (Tf)-modified DSF/copper sulfide (CuS) nanocomplex (Tf-DSF/CuS) for glioma therapy. Tf was used as glioma targeting motifs, DSF as an anticancer agent, and CuS as a source of Cu ions and a photothermal agent. Read More

Int J Pharm 2021 Sep 4;607:120972. Epub 2021 Aug 4.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849 USA. Electronic address:

Disulfiram copper complex [Cu(DDC)] nanoparticles have been explored as promising anticancer agents but with concerns of toxic side effects. To improve tumor specificity and enhance anticancer efficacy, we developed a novel [copper sulfide nanoparticle (CuS NP) + disulfiram prodrug (DQ) micelle + near-infrared (NIR) laser] (CDL) combination therapy. DQ, a reactive oxygen species (ROS)-responsive prodrug, can be selectively activated at the tumor site with elevated ROS to release DDC and form Cu(DDC)in situ. Read More

PLoS Comput Biol 2021 08 5;17(8):e1009110. Epub 2021 Aug 5.

Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.

Ethanol is one of the most widely used recreational substances in the world and due to its ubiquitous use, ethanol abuse has been the cause of over 3.3 million deaths each year. In addition to its effects, ethanol's primary metabolite, acetaldehyde, is a carcinogen that can cause symptoms of facial flushing, headaches, and nausea. Read More

Mayo Clin Proc 2021 07;96(7):2005-2007

University of Pennsylvania Health System, Philadelphia, PA.

Pharmaceutics 2021 Jun 16;13(6). Epub 2021 Jun 16.

Department of Biotherapy, Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, China.

High systemic stability and effective tumor accumulation of chemotherapeutic agents are indispensable elements that determine their antitumor efficacy. PEGylation of nanoparticles (NPs) could prolong the retention time in vivo by improving their stability in circulation, but treatment suffers reduced tumor penetration and cellular uptake of nanomedicines. The tumor microenvironment (TME)-responsive NPs maintain their stealth features during circulation and undergo a stimuli-responsive dePEGylation once exposed to the site of action, thereby achieving enhanced internalization in tumor cells. Read More

Pharmaceutics 2021 Jun 17;13(6). Epub 2021 Jun 17.

Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, University of Freiburg, Sonnenstr. 5, 79104 Freiburg, Germany.

Preclinical in vitro studies of drug candidates for anticancer therapy are generally conducted on well-established 2D cell models. Unfortunately, these models are unable to mimic the properties of in vivo tumors. However, in vitro 3D models (spheroids) have been proven to be superior in reflecting the tumor microenvironment. Read More

ACS Appl Bio Mater 2020 Oct 9;3(10):7147-7157. Epub 2020 Sep 9.

College of Nursing and Health Innovation, The University of Texas at Arlington, TX, 76019, USA.

Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide with a low 5-year survival rate. More effective chemotherapeutic drugs, either new or repurposing ones, are urgently needed. Disulfiram (DSF) is a safe and public domain drug for alcohol addiction treatment and later shown to have anti-cancer capability, especially when administrated together with copper. Read More

Eur J Pharmacol 2021 Aug 8;904:174143. Epub 2021 May 8.

Military Institute of Hygiene and Epidemiology, 01-163, Warsaw, Poland; Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research (CBP), Medical University of Warsaw, 02-097, Warsaw, Poland.

Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This drug, however, has been suggested as useful in other forms of drug addiction due to its beneficial potential in both drug abuse reduction and withdrawal. However, among other drugs used in alcohol dependence, it carries the greatest risk of pharmacological interactions. Read More