A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Female ; Male ; Humans ; Cisplatin/pharmacology* ; Disulfiram/pharmacology* ; Testicular Neoplasms/drug therapy* ; Fanconi Anemia/drug therapy* ; Alcoholism/drug therapy* ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Substance Withdrawal Syndrome/drug therapy* ; Apoptosis ; Antineoplastic Agents/therapeutic use* ; Cell Proliferation

PURPOSE: Glioblastoma, the most common brain tumor in adults, has poor prognosis. The purpose of this study was to determine the effect of disulfiram (DSF), an aldehyde dehydrogenase inhibitor, on in vitro radiosensitivity of glioblastoma cells with different methylation status of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter and the underlying mechanism of such effect. MATERIALS AND METHODS: Five human glioblastoma cells (U138MG, T98G, U251MG, U87MG, and U373MG) and one normal human astrocyte (NHA) cell were cultured and treated with DSF or 6MV X-rays (0, 2, 4, 6, and 8 Gy). For combined treatment, cells were treated with DSF before irradiation. Surviving fractions fit from cell survival based on colony forming ability. Apoptosis, DNA damage repair, and cell cycle distributionwere assayed bywestern blot for cleaved caspase-3, γH2AX staining, and flow cytometry, respectively. RESULTS: DSF induced radiosensitization in most of the glioblastoma cells, especially, in the cells with radioresistance as wildtype unmethylated promoter (MGMT-wt), but did not in normal NHA cell. DSF augmented or induced cleavage of caspase-3 in all cells after irradiation. DSF inhibited repair of radiation-induced DNA damage in MGMT-wt cells, but not in cells with methylated MGMT promoter. DSF abrogated radiation-induced G2/M arrest in T98G and U251MG cells. CONCLUSION: Radiosensitivity of glioblastoma cells were preferentially enhanced by pre-irradiation DSF treatment compared to normal cell, especially radioresistant cells such as MGMT-wt cells. Induction of apoptosis or inhibition of DNA damage repair may underlie DSF-induced radiosensitization. Clinical benefit of combining DSF with radiotherapy should be investigated in the future.
Adult ; Aldehyde Dehydrogenase ; Apoptosis ; Astrocytes ; Brain Neoplasms ; Caspase 3 ; Cell Cycle ; Cell Survival ; Disulfiram ; DNA Damage ; Flow Cytometry ; Glioblastoma ; Humans ; In Vitro Techniques ; Methylation ; Prognosis ; Radiation Tolerance ; Radiotherapy

Disulfiram has been used for the treatment of alcohol dependence for nearly 65 years and is approved by the Food and Drug Administration. It causes negative reinforcement by accumulating toxic acetaldehyde due to irreversible inhibition of aldehyde dehydrogenase. Disulfiram has very few side effects when taken without alcohol. Epileptic seizure induction is a rare side effect in therapeutic doses, and its mechanism is unknown. We present a patient with a single epileptic seizure which was thought to be due to disulfiram used in the treatment of alcohol dependence. We did not find it ethical to administer disulfiram again because the patient discontinued alcohol use and was afraid of epileptic seizures.
Acetaldehyde ; Alcoholism ; Aldehyde Dehydrogenase ; Disulfiram ; Epilepsy ; Humans ; Reinforcement (Psychology) ; United States Food and Drug Administration

BACKGROUND: NUP98 has numerous partner genes of which plant homeodomain (PHD) finger protein 23 (PHF23) fusion with NUP98 (NP23) can be detected by RT-PCR in patients with cytogenetically normal acute myelogenous leukemia (AML). In this fusion transcript of NP23 PHD of PHF23 is known to specifically bind H3K4me3 residues and act as a chromatic modifier. Disulfiram (DSF) which inhibits the binding of PHD to H3K4me3 residues selectively killed NP23 myeloblasts in vitro and therefore, we planned to evaluate the efficacy of DSF in vivo. METHODS: Cultured 961C cells (CD45.2), NP23 myeloblast cells were transplanted into B57BL/6 mice (CD45.1). Using limit dilution assay the number of leukemic stem cells (LSCs) could be calculated. A certain amount of 961C cells were transplanted into B57BL/6 mice and DSF was treated after 1 week. The engraftment level was monitored with CD45.2. Kaplan Meier survival curve was used to compare the survival between therapeutic and control group. RESULTS: 961C cells could be transplanted without radiation in recipient mice. Calculated LSC was estimated to be 1 out of 184 cells (95% CI range, 56–609). When treated with DSF of different doses and administration routes in 961C recipient mice no survival advantage of DSF was observed in 961C transplanted immunocompetent mouse, however it was evident that engraftment level was consistent in both groups. CONCLUSION: No survival advantage of DSF in 961C transplanted immunocompetent mouse was observed, however it was evident that 961C cells shared niche with normal hematopoietic stem cells (HSCs). We expect that 961C cells and transplanted recipient mice have the potential to be used as in vivo system for new drugs development as well as for research dealing with niche for normal HSCs and LSCs.
Animals ; Disulfiram ; Fingers ; Granulocyte Precursor Cells ; Hematopoietic Stem Cells* ; Humans ; In Vitro Techniques ; Leukemia, Myeloid, Acute ; Mice ; Plants ; Stem Cells

No abstract available.
Disulfiram* ; Psychotic Disorders*

Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of dopamine-betahydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis. We recommend that disulfiram should be used at the lowest effective dose, possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis.
Alcoholism ; Disulfiram* ; Dopamine ; Humans ; Metabolism ; Norepinephrine ; Psychotic Disorders*

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease (IBD). In addition, a significant number of children with IBD, particularly Crohn's disease (CD) have impaired linear growth. Nutritional support is important in patients with IBD and nutritional problems. Enteral nutrition (EN) can reduce CD activity and maintain remission in both adults and children. Given that the ultimate goal in the treatment of CD is mucosal healing, this advantage of EN over corticosteroid treatment is valuable in therapeutic decision-making. EN is indicated in active CD, in cases of steroid intolerance, in patient's refusal of steroids, in combination with steroids in undernourished individuals, and in patients with inflammatory stenosis of the small intestine. EN should be the first choice compared to total parenteral nutrition. However, EN does not have a primary therapeutic role in ulcerative colitis. In conclusion, it appears that the role of nutrition as supportive care in patients with IBD should not be underestimated. The aim of this comprehensive review is to provide the reader with an update on the role of nutritional support in IBD patients.
Adult ; Child ; Colitis, Ulcerative ; Constriction, Pathologic ; Crohn Disease ; Disulfiram ; Enteral Nutrition ; Humans ; Inflammatory Bowel Diseases* ; Intestine, Small ; Nutritional Support* ; Parenteral Nutrition, Total ; Steroids ; Thinness

OBJECTIVETo establish a method for determination of disulfiram in the workplace atmosphere by liquid chromatography.

METHODSSampling with glass fiber filter, eluting with methanol, separating with C18 column, and determination with liquid chromatography.

RESULTSThe bearing capacity of glass fiber filter exceeded 3.45 mg per piece. The elution efficiency was 97.8%∼101.0% The relative standard deviation varied from 1.09% to 1.44%. The limit of detection was 0.1 µg/ml. The minimum detectable concentration was 0.011 mg/m³ (with sampled air volume of 45 L).

CONCLUSIONThe method has high selectivity, accuracy, and precision and strong applicability.

Based on reporting in the last several years, an impressive but dismal list of cytotoxic chemotherapies that fail to prolong the median overall survival of patients with glioblastoma has prompted the development of treatment protocols designed to interfere with growth-facilitating signaling systems by using non-cytotoxic, non-oncology drugs. Recent recognition of the pro-mobility stimulus, interleukin-18, as a driver of centrifugal glioblastoma cell migration allows potential treatment adjuncts with disulfiram and ritonavir. Disulfiram and ritonavir are well-tolerated, non-cytotoxic, non-oncology chemotherapeutic drugs that are marketed for the treatment of alcoholism and human immunodeficiency virus (HIV) infection, respectively. Both drugs exhibit an interleukin-18-inhibiting function. Given the favorable tolerability profile of disulfiram and ritonavir, the unlikely drug-drug interaction with temozolomide, and the poor prognosis of glioblastoma, trials of addition of disulfiram and ritonavir to current standard initial treatment of glioblastoma would be warranted.
Antineoplastic Agents ; Dacarbazine ; analogs & derivatives ; Disulfiram ; Glioblastoma ; Humans ; Interleukin-18 ; Ritonavir

PURPOSE: The purpose of this study was to examine relationships between drinking motivation, drinking refusal self-efficacy, job stress and problem drinking, and identify contributing factors on employees' problem drinking. METHODS: A total of 191 employees recruited from two worksites. Data were analyzed using descriptive statistics, t-test, ANOVA, and Pearson's correlation coefficient, and multiple regression. RESULTS: A 65.5% of employees has shown as hazardous drinking. Employees' problem drinking was significantly influenced by coping motives as a sub-factors of drinking motives (beta=.25) and social pressure as a sub-factors of drinking refusal self-efficacy(beta =-.57), explained 51.2% of the total variance. CONCLUSION: Considering the results of this study, healthy workplace culture for preventing employees' problem drinking should be builded. In addition, alcohol education program and effective employee assistance program need to be developed.
Alcohol Drinking ; Disulfiram* ; Drinking* ; Education ; Humans ; Male ; Motivation* ; Workplace