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Nature Communications Nov 2022Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to... (Clinical Trial)
Clinical Trial
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.
Topics: Humans; Bile Acids and Salts; Clostridium; Disulfiram; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Pilot Projects
PubMed: 36369291
DOI: 10.1038/s41467-022-34671-1 -
International Journal of Antimicrobial... May 2022The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of... (Review)
Review
The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of bacterial infections. Five scientific databases (PubMed, Embase, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature) were searched to retrieve the maximum literature regarding the study's aim. The search strategy retrieved a total of 870 studies, of which 31 were included and 19 approached disulfiram as the primary aim and 12 included it as a secondary finding from other investigational objectives. The evidence pointed out five main aspects of pre-clinical testing regarding disulfiram antibacterial activity, namely spectrum of antimicrobial action, drug combinations, intracellular studies, animal studies and bacterial targets. Findings to emerge from this study are the observed potential of disulfiram as a non-antibiotic drug being proposed as a potential drug to contribute to the treatment of bacterial diseases usually with few treatment alternatives in the context of drug resistance. We evaluated the potency and selectivity of disulfiram, which indeed until now shows potential to be explored for use as an adjunctive chemical to antimicrobial ones. Even with the level of evidence being reserved, the potential of combining disulfiram with other drugs, already used or new to be used for the treatment of mycobacterial diseases, as well as its likely immunomodulatory effect, deserve to be further investigated. Furthermore, the copper-dependent mode of action in Gram-positive bacteria is an alternative to be explored in drug design or repurposing of chemicals.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Disulfiram; Gram-Positive Bacteria
PubMed: 35367599
DOI: 10.1016/j.ijantimicag.2022.106578 -
Cancer Chemotherapy and Pharmacology Feb 2021Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the... (Review)
Review
Cancer is a major health issue worldwide and the global burden of cancer is expected to reduce the costs of treatment as well as prolong the survival time. One of the promising approaches is drug repurposing, because it reduces costs and shortens the production cycle of research and development. Disulfiram (DSF), which was originally approved as an anti-alcoholism drug, has been proven safe and shows the potential to target tumours. Its anti-tumour effect has been reported in many preclinical studies and recently on seven types of cancer in humans: non-small cell lung cancer (NSCLC), liver cancer, breast cancer, prostate cancer, pancreatic cancer, glioblastoma (GBM) and melanoma and has a successful breakthrough in the treatment of NSCLC and GBM. The mechanisms, particularly the intracellular signalling pathways, still remain to be completely elucidated. As shown in our previous study, DSF inhibits NF-kB signalling, proteasome activity, and aldehyde dehydrogenase (ALDH) activity. It induces endoplasmic reticulum (ER) stress and autophagy and has been used as an adjuvant therapy with irradiation or chemotherapy drugs. On the other hand, DSF not only kills the normal cancer cells but also has the ability to target cancer stem cells, which provides a new approach to prevent tumour recurrence and metastasis. Furthermore, other researchers have reported the ability of DSF to bind to nuclear protein localization protein 4 (NPL4), induce its immobilization and dysfunction, ultimately leading to cell death. Here, we provide an overview of DSF repurposing as a treatment in preclinical studies and clinical trials, and review studies describing the mechanisms underlying its anti-neoplastic effects.
Topics: Animals; Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Neoplasms; Neoplastic Stem Cells
PubMed: 33426580
DOI: 10.1007/s00280-020-04216-8 -
Recent Patents on Anti-cancer Drug... 2019Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance... (Review)
Review
BACKGROUND
Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity.
OBJECTIVE
To summarize the anti-cancer effects of Disulfiram through a thorough patent review.
METHODS
This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy.
RESULTS
Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug.
CONCLUSION
For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.
Topics: Animals; Antineoplastic Agents; Disulfiram; Drug Repositioning; Humans; Neoplasms; Patents as Topic; Reactive Oxygen Species
PubMed: 31084595
DOI: 10.2174/1574892814666190514104035 -
Biomaterials Feb 2022Disulfiram (DSF) has been used as an alcoholism drug for 70 years. Recently, it has attracted increasing attention owing to the distinguished anticancer activity, which... (Review)
Review
Disulfiram (DSF) has been used as an alcoholism drug for 70 years. Recently, it has attracted increasing attention owing to the distinguished anticancer activity, which can be further potentiated by the supplementation of Cu. Although encouraging anticancer results are obtained in lab, the clinical outcomes of oral DSF are not satisfactory, which urges an in-depth understanding of the underlying mechanisms, bottlenecks, and proposal of potential methods to address the dilemma. In this review, a critical summarization of various molecular biological anticancer mechanisms of DSF/Cu is provided and the predicament of orally delivering DSF in clinical oncotherapy is explained by the metabolic barriers. We highlight the recent advances in the DSF/Cu delivery strategies and the emerging treatment regimens for cancer treatment. Last but not the least, we summarize the clinical trials regarding DSF and make a prospect of DSF/Cu-based cancer therapy.
Topics: Cell Line, Tumor; Copper; Disulfiram; Humans; Neoplasms
PubMed: 34979419
DOI: 10.1016/j.biomaterials.2021.121335 -
Duodecim; Laaketieteellinen... 1994
Review
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Drug Implants; Humans
PubMed: 7555786
DOI: No ID Found -
The American Journal of Medicine Jun 1990For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the... (Review)
Review
PURPOSE
For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the clinical literature regarding the risks, benefits, indications, and efficacy of this controversial drug and summarized current knowledge of this therapy.
CONCLUSIONS
Disulfiram will produce an aversive reaction with ethanol, usually at a dose between 250 mg/day and 500 mg/day, although some patients may not have an aversive reaction at this level. Cardiac, hepatic, and neurologic toxicity can also occur within this dosage range. If disulfiram is to be used, the patient must clearly understand the risks of drinking while taking the drug, and the physician and patient must agree about the need for continued clinical supervision and monitoring for efficacy and side effects. The physician must also recognize that disulfiram is only an adjunctive therapy and that continued support, supervision, and other therapeutic measures are required. Disulfiram is probably effective in reducing the frequency of alcohol consumption in the compliant patient over the short term (e.g., 6 months). Certain subgroups of patients, such as those who are older, those who are more socially stable, and those who are well-motivated, may experience a beneficial effect for longer periods. The drug may be most effective in reducing short-term alcohol consumption when the compliance of the patient is supervised, although consideration of this kind of therapy includes the practical problems of supervising the patient and concerns that the supervising person may be placed in a difficult position. Prescription of disulfiram without accompanying education, counseling, and concomitant alcoholism therapy is not beneficial. Disulfiram has no proven effect on the long-term outcome of alcoholism.
Topics: Alcoholism; Disulfiram; Ethanol; Humans
PubMed: 2189310
DOI: 10.1016/0002-9343(90)90534-k -
European Journal of Pharmacology Aug 2021Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This... (Review)
Review
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. Concomitant use of DSF and central nervous system stimulants usually leads to harmful, undesirable effects. To date, there is still limited data regarding the detailed safety profile of DSF as a concomitant drug. In this review article, we outline the current state of knowledge about DSF, its broad pharmacological action, as well as therapeutic effects, with a particular emphasis on the molecular understanding of its potential pharmacodynamic interactions with common addictive substances (e.g., alcohol, cocaine, cannabinoids, opioids) supported by relevant examples.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Alcohol Drinking; Alcoholism; Animals; Disulfiram; Drug Interactions; Humans; Substance-Related Disorders
PubMed: 33971180
DOI: 10.1016/j.ejphar.2021.174143 -
Pharmacogenetics and Genomics Dec 2023
Topics: Humans; Disulfiram
PubMed: 37728645
DOI: 10.1097/FPC.0000000000000509 -
The Journal of Nervous and Mental... Dec 1971
Review
Topics: Age Factors; Alcoholism; Antisocial Personality Disorder; Attitude; Attitude of Health Personnel; Aversive Therapy; Compulsive Behavior; Depression; Disulfiram; Drug Interactions; Fear; Follow-Up Studies; Humans; Interpersonal Relations; Motivation; Neurologic Manifestations; Physician-Patient Relations; Sex Factors; Socioeconomic Factors
PubMed: 4941777
DOI: 10.1097/00005053-197112000-00002