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

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

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

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

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*

No abstract available.
Disulfiram* ; 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

PURPOSE: A survey was conducted to assess the impact of a TED-like educational session on participants' willingness to accept dental implant therapy. MATERIALS AND METHODS: Volunteers interested in having information about dental implant therapies were recruited and asked to complete a two-part survey before and after an educational session. The initial survey elicited demographic information, self-perceived knowledge on dental implants and willingness to this kind of treatment. A "TED-style" presentation that provided information about dental implant treatments was conducted before asking the participants to complete a second set of questions assessing the impact of the session. RESULTS: The survey was completed by 104 individuals, 78.8% were women and the mean age was 66.5+/-10.8. Before the educational session, 76.0% of the participants refused dental implants mainly due to lack of knowledge. After the educational session, the rejection of dental implants decreased by almost four folds to 20.2%. CONCLUSION: This study proved that an educational intervention can significantly increase willingness to accept treatment with dental implants in a segment of the population who is interested in having information about dental implant therapy. Furthermore, educational interventions, such as TED-like talks, might be useful to increase popular awareness on dental implant therapy.
Dental Implants* ; Disulfiram ; Education, Dental ; Female ; Humans ; Volunteers

In a popular sense, Jehovah's Witnesses (JW) have their creeds, one of which is refusal of blood transfusion. Such refusal may impinge on their proper management, especially in critical situations. We present a case of successful bloodless multimodality therapy, which was performed for a JW. The patient was a 49-year-old woman and JW who had general weakness 7 days before admission. She was diagnosed with a pancreatic neuroendocrine tumor (PNET) with hepatic metastases. Transcatheter arterial chemoembolization and Sandostatin LAR injection were performed, and then she was given a transfusion-free Radical antegrade modular pancreatosplenectomy sequentially. We gave recombinant human erythropoietin and iron hydroxide sucrose complex daily for five days after surgery. She was discharged at postoperative day 12 without any surgical complications. Multimodality therapy is very important for optimal treatment of PNET. Along with intimate interdepartmental cooperation, careful patient selection and appropriate perioperative management could possibly enhance the surgical outcome.
Blood Transfusion ; Bloodless Medical and Surgical Procedures ; Disulfiram ; Erythropoietin ; Female ; Humans ; Iron ; Jehovah's Witnesses ; Middle Aged ; Neoplasm Metastasis ; Neuroectodermal Tumors, Primitive ; Neuroendocrine Tumors* ; Octreotide ; Pancreas* ; Pancreatectomy ; Patient Selection ; Sucrose

PURPOSE: A loop ileostomy is used to protect an anastomosis after anal sphincter-preserving surgery, especially in patients with low rectal cancer, but little information is available concerning risk factors associated with a nonreversal ileostomy. The purpose of this study was to identify risk factors of ileostomy nonreversibility after a sphincter-saving resection for rectal cancer. METHODS: Six hundred seventy-nine (679) patients with rectal cancer who underwent sphincter-preserving surgery between January 2004 and December 2011 were evaluated retrospectively. Of the 679, 135 (19.9%) underwent a defunctioning loop ileostomy of temporary intent, and these patients were divided into two groups, that is, a reversal group (RG, 112 patients) and a nonreversal group (NRG, 23 patients) according to the reversibility of the ileostomy. RESULTS: In 23 of the 135 rectal cancer patients (17.0%) that underwent a diverting ileostomy, stoma reversal was not possible for the following reasons; stage IV rectal cancer (11, 47.8%), poor tone of the anal sphincter (4, 17.4%), local recurrence (2, 8.7%), anastomotic leakage (1, 4.3%), radiation proctitis (1, 4.3%), and patient refusal (4, 17.4%). The independent risk factors of the nonreversal group were anastomotic leakage or fistula, stage IV cancer, local recurrence, and comorbidity. CONCLUSION: Postoperative complications such as anastomotic leakage or fistula, advanced primary disease (stage IV), local recurrence and comorbidity were identified as risk factors of a nonreversal ileostomy. These factors should be considered when drafting prudential guidelines for ileostomy closure.
Anal Canal ; Anastomotic Leak ; Comorbidity ; Disulfiram ; Fistula ; Humans ; Ileostomy* ; Multivariate Analysis* ; Postoperative Complications ; Proctitis ; Rectal Neoplasms* ; Recurrence ; Retrospective Studies ; Risk Factors*