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Drug Discovery Today Sep 2022The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials...
The current Coronavirus 2019 (COVID-19) pandemic has shown us that the pharmaceutical research community can organize and administer large nonprofit clinical trials (RECOVERY and SOLIDARITY) and achieve the swift development of common, unpatentable drugs for a new indication: in this case an old, inexpensive drug, dexamethasone, for COVID-19. Why is it that such nonprofit efforts are so rare and are not organized as a systemic, routine part of drug development in the public interest? Based on my own experience with repurposing the alcohol-abuse drug disulfiram (Antabuse) for cancer, I identify at least four serious deadlocks to development of nonprofit drugs. All of these obstacles should be addressed to leverage the potential of the COVID-19 pandemic for better future healthcare systems in all countries around the world.
Topics: COVID-19; Delivery of Health Care; Disulfiram; Humans; Organizations, Nonprofit; Pandemics
PubMed: 35667629
DOI: 10.1016/j.drudis.2022.06.001 -
Biochemical Pharmacology Dec 2020Hydrogen sulfide (HS) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase...
BACKGROUND
Hydrogen sulfide (HS) is an endogenous mammalian gasotransmitter. Cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) are the principal enzymes responsible for its biogenesis. A recent yeast screen suggested that disulfiram (a well-known inhibitor of aldehyde dehydrogenase and a clinically used drug in the treatment of alcoholism) may inhibit CBS in a cell-based environment. However, prior studies have not observed any direct inhibition of CBS by disulfiram. We investigated the potential role of bioconversion of disulfiram to bis(N,N-diethyldithiocarbamate)-copper(II) complex (CuDDC) in the inhibitory effect of disulfiram on HS production and assessed its effect in two human cell types with high CBS expression: HCT116 colon cancer cells and Down syndrome (DS) fibroblasts.
METHODS
HS production from recombinant human CBS, CSE and 3-MST was measured using the fluorescent HS probe AzMC. Mouse liver homogenate (a rich source of CBS) was also employed to measure HS biosynthesis. The interaction of copper with accessible protein cysteine residues was evaluated using the DTNB method. Cell proliferation and viability were measured using the BrdU and MTT methods. Cellular bioenergetics was evaluated by Extracellular Flux Analysis.
RESULTS
While disulfiram did not exert any significant direct inhibitory effect on any of the HS-producing enzymes, its metabolite, CuDDC was a potent inhibitor of CBS and CSE. The mode of its action is likely related to the complexed copper molecule. In cell-based systems, the effects of disulfiram were variable. In colon cancer cells, no significant effect of disulfiram was observed on HS production or proliferation or viability. In contrast, in DS fibroblasts, disulfiram inhibited HS production and improved proliferation and viability. Copper, on its own, failed to have any effects on either cell type, likely due to its low cell penetration. CuDDC inhibited HS production in both cell types studied and exerted the functional effects that would be expected from a CBS inhibitor: inhibition of cell proliferation of cancer cells and a bell-shaped effect (stimulation of proliferation at low concentration and inhibition of these responses at higher concentration) in DS cells. Control experiments using a chemical HS donor showed that, in addition to inhibiting CBS and CSE, part of the biological effects of CuDDC relates to a direct reaction with HS, which occurs through its complexed copper.
CONCLUSIONS
Disulfiram, via its metabolite CuDDC acts as an inhibitor of CBS and a scavenger of HS, which, in turn, potently suppresses HS levels in various cell types. Inhibition of HS biosynthesis may explain some of the previously reported actions of disulfiram and CuDDC in vitro and in vivo. Disulfiram or CuDDC may be considered as potential agents for the experimental therapy of various pathophysiological conditions associated with HS overproduction.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Animals; Cell Survival; Chelating Agents; Copper; Cystathionine beta-Synthase; Disulfiram; Ditiocarb; Dose-Response Relationship, Drug; Female; HCT116 Cells; Humans; Liver; Mice; Mice, Inbred BALB C; Organometallic Compounds
PubMed: 33035509
DOI: 10.1016/j.bcp.2020.114267 -
Cell Metabolism Aug 2020Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved...
Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities.
Topics: Animals; Anti-Obesity Agents; Body Weight; Diet; Disulfiram; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Rats; Rats, Sprague-Dawley
PubMed: 32413333
DOI: 10.1016/j.cmet.2020.04.019 -
The Journal of Neuroscience : the... Sep 2021Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal...
Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current () and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism. Acetaldehyde (ACD) has been considered aversive peripherally and rewarding centrally. However, whether ACD has a central aversive property is unclear. Here, we report that ACD excites the lateral habenula (LHb), a brain region associated with aversion and negative valence, through multiple cellular and molecular mechanisms. Intra-LHb ACD produces significant conditioned place aversion. These results suggest that ACD's actions on the LHb neurons might contribute to its central aversive property and new treatments targeting the LHb may be beneficial for alcoholism.
Topics: Acetaldehyde; Animals; Avoidance Learning; Disulfiram; Dopamine Antagonists; Dopamine Uptake Inhibitors; Glutamic Acid; Habenula; Male; Neurons; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Synaptic Transmission
PubMed: 34326141
DOI: 10.1523/JNEUROSCI.2913-20.2021 -
Indian Journal of Pharmacology 2022
Topics: Alcohol Drinking; Alcoholism; Disulfiram; Eating; Humans; Ischemia; Myocardial Ischemia
PubMed: 35546467
DOI: 10.4103/ijp.ijp_930_21 -
International Journal of Molecular... Oct 2022The co-crystallization of the lead(II) complex [Pb(SCNEt)] with tetraiodoethylene (CI) gave the co-crystal, [Pb(SCNEt)]∙½CI, whose X-ray structure exhibits only a...
The co-crystallization of the lead(II) complex [Pb(SCNEt)] with tetraiodoethylene (CI) gave the co-crystal, [Pb(SCNEt)]∙½CI, whose X-ray structure exhibits only a small change of the crystal parameters than those in the parent [Pb(SCNEt)]. The supramolecular organization of the co-crystal is largely determined by an interplay between Pb⋯S tetrel bonding (TeB) and I⋯S halogen bonding (HaB) with comparable contributions from these non-covalent contacts; the TeBs observed in the parent complex, [Pb(SCNEt)], remain unchanged in the co-crystal. An analysis of the theoretical calculation data, performed for the crystal and cluster models of [Pb(SCNEt)]∙½CI, revealed the non-covalent nature of the Pb⋯S TeB (-5.41 and -7.78 kcal/mol) and I⋯S HaB (-7.26 and -11.37 kcal/mol) interactions and indicate that in the co-crystal these non-covalent forces are similar in energy.
Topics: Ditiocarb; Halogens; Hydrocarbons, Iodinated; Lead; Models, Molecular
PubMed: 36233178
DOI: 10.3390/ijms231911870 -
Advanced Science (Weinheim,... Mar 2022Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with...
Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patient ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (Ishikawa ) mimicking hyperglycemia in patient . Subsequently, it is discovered that Ishikawa exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of Ishikawa by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits Ishikawa proliferation though Ishikawa is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of Ishikawa as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (mice ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of mice . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patients .
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus; Disulfiram; Endometrial Neoplasms; Female; Humans; Metformin; Mice; Morpholines; Nanoparticles
PubMed: 35064767
DOI: 10.1002/advs.202104472 -
Oncology Research 2023Various therapeutic strategies have been developed to overcome ovarian cancer. However, the prognoses resulting from these strategies are still unclear. In the present...
Various therapeutic strategies have been developed to overcome ovarian cancer. However, the prognoses resulting from these strategies are still unclear. In the present work, we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells. Among these, we identified disulfiram (DSF), an old alcohol-abuse drug, as a potential inducer of cell death in ovarian cancer. Mechanistically, DSF treatment significantly reduced the expression of the anti-apoptosis marker B-cell lymphoma/leukemia-2 (Bcl-2) and increase the expression of the apoptotic molecules Bcl2 associated X (Bax) and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis. Furthermore, DSF is a newly identified effective copper ionophore, thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment. Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins (biomarkers of cuproptosis). , DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model. Thus, the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.
Topics: Animals; Female; Humans; Mice; Carcinoma, Ovarian Epithelial; Cell Death; Copper; Disulfiram; Drug Repositioning; Ovarian Neoplasms; Apoptosis
PubMed: 37305383
DOI: 10.32604/or.2023.028694 -
Communications Biology Aug 2023The increasing incidence of bacterial infections caused by multidrug-resistant (MDR) Gram-negative bacteria has deepened the need for new effective treatments....
The increasing incidence of bacterial infections caused by multidrug-resistant (MDR) Gram-negative bacteria has deepened the need for new effective treatments. Antibiotic adjuvant strategy is a more effective and economical approach to expand the lifespan of currently used antibiotics. Herein, we uncover that alcohol-abuse drug disulfiram (DSF) and derivatives thereof are potent antibiotic adjuvants, which dramatically potentiate the antibacterial activity of carbapenems and colistin against New Delhi metallo-β-lactamase (NDM)- and mobilized colistin resistance (MCR)-expressing Gram-negative pathogens, respectively. Mechanistic studies indicate that DSF improves meropenem efficacy by specifically inhibiting NDM activity. Moreover, the robust potentiation of DSF to colistin is due to its ability to exacerbate the membrane-damaging effects of colistin and disrupt bacterial metabolism. Notably, the passage and conjugation assays reveal that DSF minimizes the evolution and spread of meropenem and colistin resistance in clinical pathogens. Finally, their synergistic efficacy in animal models was evaluated and DSF-colistin/meropenem combination could effectively treat MDR bacterial infections in vivo. Taken together, our works demonstrate that DSF and its derivatives are versatile and potent colistin and carbapenems adjuvants, opening a new horizon for the treatment of difficult-to-treat infections.
Topics: Animals; Colistin; Carbapenems; Meropenem; Disulfiram; Anti-Bacterial Agents; Drug Combinations; Gram-Negative Bacteria
PubMed: 37537267
DOI: 10.1038/s42003-023-05173-7 -
International Journal of Molecular... Jan 2023In the process of assisted reproduction, the high-oxygen in vitro environment can easily cause oxidative damage to oocytes. Disulfiram (DSF) can play an anti-oxidant or...
In the process of assisted reproduction, the high-oxygen in vitro environment can easily cause oxidative damage to oocytes. Disulfiram (DSF) can play an anti-oxidant or pro-oxidant role in different cells, and the effect of DSF on oocytes remains unclear. Moreover, it remains unclear whether the use of DSF in the early stages of pregnancy has a negative impact on the fetus. In this study, we found that DSF increased serum FSH levels and increased the ovulation rate in mice. Moreover, DSF enhanced the antioxidant capacity of oocytes and contributed to the success rate of in vitro fertilization. Moreover, the use of DSF in early pregnancy in mice increased the uterine horn volume and the degree of vascularization, which contributed to a successful pregnancy. In addition, it was found that DSF regulated the mRNA expression of angiogenesis-related genes (), follicular development-related genes (, and ), ovulation-related genes (, and ) and antioxidant-related genes ( and ). These results indicate that DSF is helpful for increasing the antioxidant capacity of oocytes and the ovulation rate. In early pregnancy in mice, DSF promotes pregnancy by increasing the degree and volume of uterine vascularization.
Topics: Mice; Female; Animals; Disulfiram; Antioxidants; Oxidative Stress; Reactive Oxygen Species; Reproduction; Cell Line, Tumor
PubMed: 36768698
DOI: 10.3390/ijms24032371