生物活性

• 描述Aldehyde dehydrogenase can catalyze the oxidation of aldehydes by converting them to carboxylic acids, which leave the liver and are metabolized by the body's muscle and heart. Thus the accumulation of aldehydes do harm to human. Disulfiram (DSF) is currently a clinical used inhibitor for aldehyde dehydrogenase treating alcoholism with average IC50 value of 300 nM. Moreover, studies showed that DSF may also have antitumor and chemosensitizing activities. DSF treatment could inhibit growth of TNBC cells by increasing cell death and senescence and induced 38% cell death after 72 hrs treatment combined with doxorubicin. Besides, DSF also caused many MDA-MB-231 cells death and enlarged cell morphology, showing 23% X-gal-positive cells. Cancer stem cells (CSCs) in TNBC cell lines were inhibited by 5% with DSF treatment alone or by 65% with combined treatment with doxorubicin.^[1] In purified rabbit 20S proteasome assay, DSF-copper complex inhibited the chymotrypsin-like activity with an IC50 value of 7.5 μM while DSF alone had no effect even at concentration of 20 μM. The complex also led to 95% reduction of the proteasomal chymotrypsin-like activity in the breast cancer cells and inhibited proliferation of MDA-MB-231 cells by 55%, 65% and 85% when the concentrations were 5, 10, 20 μM respectively. Besides, the complex induced apoptotic cell death due to the detection of PARP cleavage in the breast cancer cells, suggesting that the copper ion should be responsible for the inhibiting ability of DSF. Treated the MCF-10A (normal cells) and MCF10DCIS.com cell lines (malignant cells) with 20 μM the complex led to 97% reduction of proteasomal chymotrypsin-like activity in MCF10DCIS.com cell lines but no effect on the MCF-10A cell lines, suggesting the nontoxic effect of the DSF-copper complex in normal cells. The CuCl2-precultured MDA-MB-231 cells treated with 20 μM DSF also showed 67% inhibition of the proteasomal activity as well as the accumulation of PARP cleavage, suggesting copper ion is important for DSF treatment. Furthermore, DSF-treated tumors resulted in 74% inhibition of tumor growth and 87% inhibition of the proteasomal activity^[2] . Disulfiram potently inhibited GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1β secretion in human and mouse cells. It covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation^[3]. It also works as a pyroptosis inhibitor by blocking gasdermin D pore formation^[4].
• 作用机制Disulfiram is capable of binding copper react with sulfhydryl groups.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CHO cells	-	Function assay	-	Agonist activity at human TRPA1 channel expressed in CHO cells assessed as increase in intracellular calcium levels, EC50=3 μM	20356305
  human MCF10A cells	-	Proliferation assay	72 h	Antiproliferative activity against human MCF10A cells after 72 hrs by MTT assay, IC50=10 μM	20222671
  human MDA-MB-231 cells	-	Proliferation assay	72 h	Antiproliferative activity against human MDA-MB-231 cells expressing BCA2 and ERalpha after 72 hrs by MTT assay, IC50=0.32 μM	20222671

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• 动物研究
  剂量	Rat: 25 mg/kg - 125 mg/kg[5] (i.p.) Rabbit: 7.5 mg/kg[6] (i.v.)
  给药途径	i.p., i.v.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00372749	Alcoholic Intoxication, Chroni... more >>c Collapse <<	Not Applicable	Completed	-	France ... more >> Hopital Emile Roux APHP Limeil-Brevannes, France, 94450 Collapse <<
  NCT02309801	Healthy	Phase 1	Completed	-	Spain ... more >> Parc de Salut Mar. Barcelona, Spain, 08003 Collapse <<
  NCT02770378	Glioblastoma	Phase 1	Active, not recruiting	March 2020	Germany ... more >> University of Ulm School of Medicine Ulm, Baden-Württemberg, Germany, 89081 Collapse <<

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• 参考文献

• [1] Robinson TJ, Pai M, et al. High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: interaction with IQ motif-containing factors. Cell Cycle. 2013;12(18):3013-24.

  [2] Chen D, Cui QC, et al. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006;66(21):10425-33.

  [3] Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D

  [4] Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, Ruan J, Luo X, Lou X, Bai Y, Wang J, Hollingsworth LR, Magupalli VG, Zhao L, Luo HR, Kim J, Lieberman J, Wu H. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020 Jul;21(7):736-745. doi: 10.1038/s41590-020-0669-6. Epub 2020 May 4. PMID: 32367036; PMCID: PMC7316630.

  [5] Karamanakos PN, Pappas P, et al. Differentiation of disulfiram effects on central catecholamines and hepatic ethanol metabolism. Pharmacol Toxicol. 2001 Feb;88(2):106-10.

  [6] Fossa AA, Carlson GP, et al. Antiarrhythmic effect of disulfiram in various cardiotoxic models. Pharmacology. 1983;26(3):164-71.

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