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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
Joyce Heung, Johannes Yin-Kwong Poon, Chi-Kwong Tung, Sze-Wing Yeung, Ming Lam
No abstract text is available yet for this article.
March 13, 2018: Alcohol and Alcoholism: International Journal of the Medical Council on Alcoholism
Danny C Lenstra, Abbas H K Al Temimi, Jasmin Mecinović
Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site...
February 24, 2018: Bioorganic & Medicinal Chemistry Letters
Xiangchou Yang, Rongxin Yao, Hong Wang
Studies employing mouse transplantation have illustrated the role of aldehyde dehydrogenase (ALDH) defining hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs). Besides being a molecular marker, ALDH mediates drug resistance in AML, which induces poor prognosis of the patients. In AML patients, either CD34+ ALDHbr population or CD34+ CD38- ALDHint population was found to denote LSCs and minimal residual disease (MRD). A bunch of reagents targeting ALDH directly or indirectly have been evaluated. ATRA, disulfiram, and dimethyl ampal thiolester (DIMATE) are all shown to be potential candidates to open new perspective for AML treatment...
2018: BioMed Research International
Linlin Miao, Jia Su, Xuezhi Zhuo, Lifeng Luo, Yihan Kong, Jingxin Gou, Tian Yin, Yu Zhang, Haibing He, Xing Tang
The clinical application of disulfiram (DSF) in cancer treatments is hindered by its rapid degradation in the blood circulation. In this study, methoxy poly(ethyleneglycol)-b-poly(lactide-co-glycolide)/poly(ε-caprolactone) (mPEG5k-b-PLGA2k/PCL3.4k) micelles were developed for encapsulation of DSF -by using the emulsification-solvent diffusion method. Medium chain triglyceride (MCT) was incorporated into the mixed polymeric micelles to improve drug loading by reducing the core crystallinity. Differential scanning calorimetry (DSC) results implied that DSF is likely present in an amorphous form within the micelles, and is well dispersed...
March 5, 2018: Molecular Pharmaceutics
Imran Shair Mohammad, Wei He, Lifang Yin
PURPOSE: A multidrug resistance (MDR) modulator, disulfiram (DSF), was incorporated into pure paclitaxel (PTX) nanoparticles to construct a smart paclitaxel-disulfiram nanococrystals (PTX-DSF Ns) stabilized by β-lactoglobulin (β-LG), with the aim to reverse MDR and therefore enhnce cytotoxicity towards Taxol-resistant A549 cells (A549/TAX). METHOD: PTX-DSF Ns was prepared by antisolvent precipitation method. Flow cytometry was used to determine the cell uptake, drug efflux inhibition, cell cycle phase arrest and apoptosis...
February 27, 2018: Pharmaceutical Research
Anna de Cordé, Paweł Krząścik, Renata Wolińska, Patrycja Kleczkowska, Małgorzata Filip, Magdalena Bujalska-Zadrożny
Taking opioids is often accompanied by the development of dependence. Unfortunately, treatment of opioid dependence is difficult, particularly because of codependence - for example, on alcohol or other drugs of abuse. In the presented study, we analyzed the potential influence of disulfiram, a drug used to aid the management of alcoholism, on opioid abstinence syndrome, which occurs as a result of opioid withdrawal. Opioid dependence in mice was induced by subcutaneous administration of either morphine or methadone at a dose of 48 mg/kg for 10 consecutive days...
February 16, 2018: Behavioural Pharmacology
Robert M Gill, Marisa O'Brien, Adrian Young, Danielle Gardiner, Ryan J Mailloux
Protein S-glutathionylation is a reversible redox modification that regulates mitochondrial metabolism and reactive oxygen species (ROS) production in liver and cardiac tissue. However, whether or not it controls ROS release from skeletal muscle mitochondria has not been explored. In the present study, we examined if chemically-induced protein S-glutathionylation could alter superoxide (O2●-)/hydrogen peroxide (H2O2) release from isolated muscle mitochondria. Disulfiram, a powerful chemical S-glutathionylation catalyst, was used to S-glutathionylate mitochondrial proteins and ascertain if it can alter ROS production...
2018: PloS One
Dhanashree Peddawad, Shashank Nagendra, Rudrarpan Chatterjee, Hina Faldu, Akash Chheda
No abstract text is available yet for this article.
February 9, 2018: Neurology
Thomas Münzel, Andreas Daiber
Mitochondrial aldehyde dehydrogenase (ALDH-2) plays a major role in the ethanol detoxification pathway by removing acetaldehyde. Therefore, ALDH-2 inhibitors such as disulfiram represent the first therapeutic targeting of ALDH-2 for alcoholism therapy. Areas covered: Recently, ALDH-2 was identified as an essential bioactivating enzyme of the anti-ischemic organic nitrate nitroglycerin, bringing ALDH-2 again into the focus of clinical interest. Mechanistic studies on the nitroglycerin bioactivation process revealed that during bioconversion of nitroglycerin and in the presence of reactive oxygen and nitrogen species the active site thiols of ALDH-2 are oxidized and the enzyme activity is lost...
February 10, 2018: Expert Opinion on Therapeutic Targets
Hanumantha Rao Madala, Surendra R Punganuru, Francis Ali-Osman, Ruiwen Zhang, Kalkunte S Srivenugopal
There is great interest in repurposing disulfiram (DSF), a rapidly metabolizing nontoxic drug, for brain cancers and other cancers. To overcome the instability and low therapeutic efficacy, we engineered passively-targeted DSF-nanoparticles (DSFNPs) using biodegradable monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid (mPEG-PLGA) matrix. The physicochemical properties, cellular uptake and the blood brain-barrier permeability of DSFNPs were investigated. The DSFNPs were highly stable with a size of ∼70 nm with a >90% entrapment...
January 9, 2018: Oncotarget
Muddasarul Hoda, Shamim Akhtar Sufi, Bindumadhuri Cavuturu, Rukkumani Rajagopalan
Aim: Stabilizers are known to be an integral component of polymeric nanostructures. Ideally, they manipulate physicochemical properties of nanoparticles. Based on this hypothesis, we demonstrated that disulfiram (drug) and Poly-lactide-co-glycolide (polymer) interactions and physicochemical properties of their nanoparticles formulations are significantly influenced by the choice of stabilizers. Methodology: Electron microscopy, differential scanning calorimetry, x-ray diffraction, Raman spectrum analysis, isothermal titration calorimetry and in silico docking studies were performed...
February 2018: Future Science OA
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
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
Sven Reinhardt, Nicolai Stoye, Mathias Luderer, Falk Kiefer, Ulrich Schmitt, Klaus Lieb, Kristina Endres
ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an alpha-secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPP-alpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer's disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy...
January 22, 2018: Scientific Reports
Jon E Grant, Marc N Potenza, Shane W Kraus, Ismene L Petrakis
BACKGROUND: Disordered gambling behavior frequently co-occurs with alcohol dependence and other psychiatric conditions. Using data from a previously published trial, we conducted secondary analyses to examine the influence of problem-gambling features on treatment outcome for alcohol dependence or co-occurring psychopathology assessed via DSM-IV criteria. METHODS: Two hundred fifty-four patients with alcohol dependence and co-occurring psychiatric disorders were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics from October 1998 to March 2002...
November 2017: Journal of Clinical Psychiatry
Thomas Sandberg, Christian Weinberger, Didem Şen Karaman, Jessica M Rosenholm
The interaction between disulfiram (Antabus®) and silica was studied experimentally by adsorption from apolar solvent onto highly porous silica material (Santa Barbara Amorphous material-3, SBA-3) with large surface area. The adsorption isotherm was fitted to the Langmuir model by accounting two different affinities contributing to the overall behavior, which were attributed to two different types of silanol groups (i.e. geminal and vicinal) present on amorphous silica surfaces. This assumption was supported by theoretical calculations...
December 28, 2017: Journal of Pharmaceutical Sciences
Min-Han Lin, David C Moses, Chih-Hua Hsieh, Shu-Chun Cheng, Yau-Hung Chen, Chiao-Yin Sun, Chi-Yuan Chou
Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV...
December 28, 2017: Antiviral Research
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
Andrew C Naglich, Austin Lin, Sidarth Wakhlu, Bryon H Adinoff
BACKGROUND: Previous reviews have examined the use of theoretically supported combinations of drugs for the treatment of alcohol use disorder. This review seeks to examine the strengths and limitations of current clinical evidence for the use of combined pharmacological interventions intended to treat alcohol use disorder. OBJECTIVES: The objective of this review was to identify combinations of pharmacological treatments for alcohol use disorder, and assess the strength of clinical evidence for these treatments...
December 22, 2017: CNS Drugs
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