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Background. Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4 + T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4 + T cells at concentrations achieved in vivo. Methods. We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1–infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4 + T cells. Results. Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate post-dose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01). Conclusions. Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.

Pathologic alcohol use affects more than 2 billion people and accounts for nearly 6% of all deaths worldwide. There are three medications approved for the treatment of alcohol use disorder by the US Food and Drug Administration (FDA): disulfiram, naltrexone (oral and long-acting injectable), and acamprosate. Of growing interest is the use of anticonvulsants for the treatment of alcohol use disorder, although currently none are FDA approved for this indication. Baclofen, a γ-aminobutyric acid B receptor agonist used for spasticity and pain, received temporary approval for alcohol use disorder in France. Despite effective pharmacotherapies, less than 9% of patients who undergo any form of alcohol use disorder treatment receive pharmacotherapies. Current evidence does not support the use of pharmacogenetic testing for treatment individualization. The objective of this review is to provide knowledge on practice parameters for evidenced-based pharmacologic treatment approaches in patients with alcohol use disorder.

Background Disulfiram and metals inactivate key oncoproteins resulting in anti-neoplastic activity. The goal of this study was to determine the maximum tolerated dose of copper when administered with disulfiram in patients with advanced solid tumors and liver involvement. Methods Disulfiram 250 mg was administered daily in 28-day cycles. Four doses of copper gluconate were tested (2, 4, 6, and 8 mg of elemental copper) in a standard 3 + 3 dose escalation design. Patients were evaluated for dose limiting toxicities and response. Protein S -glutathionylation was evaluated as a pharmacodynamic marker. Results Twenty-one patients were enrolled and 16 patients were evaluable for dose limiting toxicities. Among the 21 patients, there was a median of 4 lines of prior chemotherapy. Five Grade 3 toxicities were observed (anorexia, elevated aspartate aminotransferase or AST, elevated alkaline phosphatase, fever, and fatigue). Response data was available for 15 patients. Four patients had stable disease with the longest duration of disease control being 116 days. The median duration of treatment for evaluable patients was 55 days (range 28–124). Reasons for discontinuation included functional decline, disease progression, and disease-associated death. Increased S -glutathionylation of serum proteins was observed with treatment. Conclusion Disulfiram 250 mg daily with copper gluconate (8 mg of elemental copper) was well-tolerated in patients with solid tumors involving the liver and was not associated with dose limiting toxicities. While temporary disease stabilization was noted in some patients, no objective responses were observed. Treatment was associated with an increase in S -glutathionylation suggesting that this combination could exert a suppressive effect on cellular growth and protein function. Trial registration NCT00742911 , first posted 28/08/2008.

Disulfiram (DSF) reduces insulin resistance and weight gain in obese mice. However, the effect on adipose tissue is unexplored due to their high instability under physiological conditions, limiting clinical applications. Thus, it is meaningful to develop a DSF carrier for sustained release to adipose tissue. We optimized the synthesis of poly-ε-caprolactone (PCL) nanoparticles (NPs) loaded with DSF and analyzed their effect on adipose tissue cells in vitro. The NPs were synthesized by nanoprecipitation method, varying its solvent, either acetone or acetone/dichloromethane (60:40) (v/v), and ratio PCL:DSF (w/w) 1:2, 1:1, 2:1 and, 1:0; finding the best condition was obtained with acetone/dichloromethane solvent mixture and 2:1 PCL:DSF. Then, NPs toxicity was analyzed on adipose cells (preadipocytes, white-like adipocytes, and macrophages) assessing association and internalization, cell viability, and cell death mechanism. NPs were spherical with a particle size distribution of 203.2 ± 29.33 nm, a ζ-potential of -20.7 ± 4.58 mV, a PDI of 0.296 ± 0.084, and a physical drug loading of 18.6 ± 5.80%. Sustained release was observed from 0.5 h (10.94 ± 2.38%) up to 96 h (91.20 ± 6.03%) under physiological conditions. NPs internalize into macrophages, white-like adipocytes and preadipocytes without modifying cell viability on white-like adipocytes and macrophages. Preadipocytes reduce cell viability, inducing mitochondrial damage, increased mitochondrial reactive oxygen species production and loss of mitochondrial membrane potential, leading to effector caspases 3/7 cleaved, resulting in apoptosis. Finally, long-term proliferation inhibition was observed, highlighting the bioequivalent effect of PCL-DSF NPs compared to free DSF. Our data demonstrated the biological interaction of PCL NPs with adipose cells in vitro. The selective cytotoxicity of DSF towards preadipocytes resulted in milder effects when it was delivered nanoencapsulated compared to the free drug. These results suggest promising pharmacological alternatives for DSF long-term delivery on adipose tissue.

Background A folate-receptor-targeted poly (lactide-co-Glycolide) (PLGA)-Polyethylene glycol (PEG) nanoparticle is developed for encapsulation and delivery of disulfiram into breast cancer cells. After a comprehensive characterization of nanoparticles, cell cytotoxicity, apoptosis induction, cellular uptake and intracellular level of reactive oxygen species are analyzed. In vivo acute and chronic toxicity of nanoparticles and their efficacy on inhibition of breast cancer tumor growth is studied. Results The folate-receptor-targeted nanoparticles are internalized into the cells, induce reactive oxygen species formation, induce apoptosis and inhibit cell proliferation more efficiently compared to the untargeted nanoparticles. The acute and toxicity test show the maximum dose of disulfiram equivalent of nanoparticles for intra-venous injection is 6 mg/kg while show significant decrease in the breast cancer tumor growth rate. Conclusion It is believed that the developed formulation could be used as a potential vehicle for successful delivery of disulfiram, an old and inexpensive drug, into breast cancer cells and other solid tumors. Graphical abstract Disulfiram, an old and inexpensive drug, is encapsulated in folate-targeted PLGA-PEG nanoparticles and delivered into breast cancer cells using passive and active targeting to inhibit tumor growth in mice

PurposeThis work aims to create a novel Cu2+ liposome with excellent loading stability and develop synergistic effect with disulfiram (DSF) for the treatment of tumor.MethodsCopper oleate was incorporated into the liposome membrane via alcohol injection method in this work. In vitro release test was applied to evaluate the release profile of the liposomes. Pharmacokinetic studies were performed in rats and the antitumor efficacy was assessed in mice bearing hepatoma xenografts.ResultsThe copper oleate liposome (Cu(OI)2-L) was formulated and the loading efficiency were more than 85%. TEM images confirmed that the Cu(OI)2-L had a spherical morphology with an average diameter of 100 nm. Cu(OI)2-L displayed a biphasic release profile, with >70% retained drug over 8 h incubation in PBS at pH 7.4. Pharmacokinetic studies demonstrated that Cu(OI)2-L had a prolonged circulation time and increased AUC when compared to the injection of copper oleate solution. The antitumor efficacy test demonstrated an enhanced tumor inhibition rate with the treatment of Cu(OI)2-L and DSF nanoparticles, indicating an improved synergistic antitumor effect.ConclusionsThe Cu(OI)2-L was suitable to be employed in combination with disulfiram for tumor treatment and can also open up opportunities for targeted delivery of copper.

Background Melanoma poses a significant threat to human health, making the development of a safe and effective treatment a crucial challenge. Disulfiram (DS) is a proven anticancer drug that has shown effectiveness when used in combination with copper (DS-Cu complex). Objectives This study focuses on encapsulation of DS-copper complex into nanofiber scaffold from polyvinyl alcohol (PVA) (DS-Cu@PVA). In order to increase bioavailability towards melanoma cell lines and decrease its toxicity. Methods The scaffold was fabricated through an electrospinning process using an aqueous solution, and subsequently analyzed using ART-Fourier transform infrared spectroscopy (ART-FTIR), scanning electron microscopy (SEM), and energy dispersive X-ray analysis (EDX). Additionally, cellular cytotoxicity, flow cytometry analysis, and determination of caspase 3 activity were conducted to further characterize the scaffold. Results The results confirmed that encapsulation of DS-Cu complex into PVA was successful via different characterization. The scanning electron microscopy (SEM) analysis revealed that the diameter of the nanofibers remained consistent despite the addition of DS-Cu. Additionally, ATR-FTIR confirmed that the incorporation of DS-Cu into PVA did not significantly alter the characteristic peaks of PVA. Furthermore, the cytotoxicity assessment of the DS-Cu@PVA nanofibrous scaffold using human normal skin cells (HFB4) demonstrated its superior biocompatibility compared to DS-Cu-free counterparts. Notably, the presence of DS-Cu maintained its effectiveness in promoting apoptosis by increasing cellular reactive oxygen species, proapoptotic gene expression, and caspase 3 activity, while simultaneously reducing glutathione levels and oncogene expression in human and mouse melanoma cell lines (A375 and B16F10, respectively). Overall, these findings suggest that the addition of DS-Cu to PVA nanofibers enhances their biocompatibility and cytotoxic effects on melanoma cells, making them a promising candidate for biomedical applications. Conclusion The findings indicate that the targeted delivery of DS-Cu onto a PVA nanofiber scaffold holds potential approach to enhance the efficacy of DS-Cu in combating melanoma. Graphical abstract

Tumor initiating cells (TIC) have been suggested as a mechanism for driving chemoresistance and tumor recurrence in human cancers including triple negative breast cancer (TNBC). Significant progress has been made in targeting TICs. However, methods for simultaneously targeting heterogeneous TIC populations are lacking. In this study, we found that treating TNBC cells with chemotherapeutic agents led to a significant accumulation of the ALDH + TIC population. Treating TNBC cells with a disulfiram and copper mixture (DSF/Cu) specifically decreased the ALDH + TIC population and treatment with BKM120, a pan-PI3K inhibitor, significantly decreased the CD44 + /CD24 − TIC population. Furthermore, treatment with DSF/Cu or BKM120 induced higher levels of apoptosis in ALDH + or CD44 + /CD24 − populations, respectively, than in bulk tumor cells. Combining DSF/Cu and BKM120 treatment simultaneously decreased the ALDH + and CD44 + /CD24 − TICs. Using a TNBC tumor xenograft mouse model, we found that DSF/BKM in combination with Taxol significantly reduced the tumor burden and delayed tumor recurrence compared to Taxol treatment alone. Our study is the first of its kind to use two different drugs to abolish two major TIC subtypes simultaneously and inhibit tumor recurrence. These results lay a foundation for developing a novel therapy that can improve chemotherapeutic efficacy.

In this study, poly(lactic- -glycolic acid) (PLGA) was used as a carrier to construct disulfiram-loaded porous microparticle through the emulsion solvent evaporation method, using ammonium bicarbonate as a porogen. The microparticle possessed highly porous surface, suitable aerodynamic diameter for inhalation (8.31±1.33 µm), favorable drug loading (4.09%±0.11%), and sustained release profile. The antiproliferation effect of release supernatant was detected through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using non-small-cell lung cancer A549 as a model, with only 13.3% of cell viability observed for the release supernatant at 7 days. The antiproliferation mechanism was elucidated to be associated with the enhanced induction of cell apoptosis and cell cycle arrest at S phase through flow cytometry and Western blotting analysis. Finally, wound healing and transwell migration assay showed that they could efficiently inhibit the cell migration. These results demonstrated that disulfiram-loaded porous PLGA microparticle could achieve favorable antitumor efficiency, implying the potential of treating non-small-cell lung cancer in a pulmonary administration.

The elevated level of copper is one of the hallmark features of cancer cells in most of the types of cancer. In the present study, this feature has been targeted to investigate if coadministration of exogenous copper (Cu+) and its chelating agent like disulfiram (DSF+) influence the antineoplastic activity of the anticancer drug, Gleevec (GLV+), in hepatocellular carcinoma (HCC)-induced rats via immunomodulation. After the treatment, the level of proinflammatory interleukins (IL-1, 2, 6, and 7), anti-inflammatory interleukin (IL-10) concomitant with transcription factors (NF-kB and TNF-a), and the apoptotic marker (cleaved PARP) was estimated. The cancer-induced group without treatment (CN+) demonstrated abnormally elevated level of all proinflammatory cytokines and transcription factors concomitant with a compromised level of cleaved PARP as compared to the control normal (CN-). The detailed histological analysis also supported the results exhibiting extensive inflammation and tissue fibrosis confirming the second stage of HCC. Cu+, DSF+, and GLV+ displayed mild improvement in most of the parameters, but the combination group GLV + Cu+ demonstrated remarkable recovery in histology and most of the parameters tended towards the CN- followed by GLV + DSF+. Therefore, the management of copper level is critical in realizing the antineoplastic activity of GLV up to its full potential in cancer treatment. These findings will help in improving chemoimmunotherapy and personalized cancer treatment.