Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways

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 Bcell 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).In vivo,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.

Disulfiram联合Cu对耐药白血病细胞的作用及与JNK通路的关系

目的研究disulfiram(DS)联合Cu(DS/Cu)对耐药白血病细胞株HL60/ADM的逆转耐药作用及与JNK通路的关系。方法MTT法检测DS/Cu对HL60/ADM细胞的增殖抑制作用;选取DS/Cu对HL-60/ADM无明显杀伤作用的IC20值作为逆转浓度,MTT法检测IC20浓度DS/Cu联合不同浓度ADM处理24h后的IC50值;流式细胞仪检测阿霉素、DS/Cu单药及DS/Cu与阿霉素联合处理HL-60/ADM24h凋亡细胞比例的变化;Westernblotting检测c-jun表达的变化。结果DS/Cu对HL60/ADM细胞具有显著的增殖抑制作用,处理24hIC50为(1.11±0.025)μmol/L。HL-60/ADM细胞经IC20浓度(0.63μmol/L)DS/Cu处理24h后,ADM的IC50值从(7.69±1.87)降到(0.48±0.021)μg/mL,逆转倍数为15.95倍(P=0.003)。0.63μmol/L的DS/Cu、1.25μg/mL的阿霉素单药及上述浓度的DS/Cu联合阿霉素作用HL60/ADM细胞24h后,联合组凋亡细胞比例较DS/Cu或阿霉素单药组均显著增多(P<0.05)。Westernblotting显示阿霉素联合DS/Cu作用24h后c-jun表达水平显著增加。结论DS/Cu在体外对HL60/ADM细胞具有杀伤作用,IC20浓度的DS/Cu能够有效逆转HL60/ADM细胞的耐药,活化JNK通路是其机制之一。

Disulfiram及联合Cu对急性淋巴细胞白血病Molt4细胞增殖、凋亡及MDR1基因表达的影响

目的为进一步了解Disulfiram(DS)及DS联合Cu(DS/Cu)对急性淋巴细胞白血病Molt4细胞增殖、凋亡及多药耐药1(MDR1)基因水平表达的影响。方法用MTT法检测不同浓度(0.125、0.250、0.500、1.000、2.000、4.000μmol/mL)DS和DS/Cu对Molt4细胞的增殖抑制作用;用Annexin-ⅴ-FITC/PI流式细胞术检测不同浓度DS和DS/Cu作用Molt4细胞24h后凋亡细胞比例;实时荧光定量PCR检测不同浓度DS和DS/Cu对Molt4细胞MDR1基因表达水平的影响。结果不同浓度的DS对Molt4细胞有一定的抑制增殖作用,且呈剂量依赖性,IC50为(1.370±0.263)μmol/mL。DS/Cu联合后对Molt4细胞增殖抑制作用显著增强,IC50降为(0.560±0.443)μmol/mL,DS/Cu对Molt4细胞的抑制作用显著高于DS单药(P=0.005)。DS单药及DS/Cu对Molt4细胞均有诱导凋亡的作用,但DS/Cu对诱导Molt4细胞凋亡的比例显著高于DS单药(P=0.01)。DS单药对Molt4细胞MDR1基因表达水平无明显影响,而DS/Cu能显著降低Molt4细胞MDR1基因表达水平(P<0.001)。结论 DS对Molt4细胞有一定的抑制增殖、诱导凋亡作用,但对Molt4细胞MDR1表达水平无明显影响。DS/Cu不仅对Molt4细胞抑制增殖、诱导凋亡作用显著增强,还可显著下调Molt4细胞MDR1基因表达水平。

Disulfiram thermosensitive in-situ gel based on solid dispersion for cataract

To improve the corneal permeability and water-solubility of disulfiram(DSF), which is an ocular drug for cataract, P188 was selected as a matrix to prepare solid dispersion of DSF(DSF SD) by hot melt method. The DSF SD was characterized by DSC, XRD, and IR, and the results suggested that DSF was amorphous in DSF SD. The DSF SD was added to borate buffer solution(BBS) contained 20% poloxamer P407 and 1.2% poloxamer P188 to form in-situ gel. In vitro and in vivo experiments revealed that DSF SD combined with in-situ gel(DSF SD/in-situ gel) increased the residence time and the amount of DSF penetrated through the corneal. The pharmacodynamics studies exhibited DSF SD/in-situ gel delayed the development of selenium-induced cataract at some content. These results investigated that DSF SD/in-situ gel as a drug delivery system can improve DSF ocular permeability.

Disulfiram in the management of alcohol dependence: A comprehensive clinical review

Disulfiram remains a viable option as a treatment for alcohol dependence and has been shown in recent studies to be successful in treating patients with alcohol dependence in a manner that is superior to both naltrexone and acamprosate. It is also useful in dual diagnosis patients and those with co-morbid cocaine and alcohol dependence. Although disulfiram’s mechanism of action in alcohol dependence was long thought to be its effects as a psychological deterrent, more recent studies have uncovered potential anticraving effects as well. Recent reviews exhort to the importance of supervised disulfiram therapy in highlighting many of the potential and unique benefits of disulfiram. The present article will review the major clinical trials of disulfiram spanning nearly 60 years. It also discusses the usage of disulfiram across diverse populations along with monitoring for compliance and various adverse effects that may be encountered. The paper also reviews certain studies on long acting disulfiram therapy, recent comparative trials of disulfiram and its use in alcohol dependence. The review concludes with the role of disulfiram in the present day and long-term pharmacotherapy of alcohol dependence along with future research needs in this area.

Disulfiram’s Antineoplastic Effects on Ovarian Cancer

Objective: Aldehyde dehydrogenase (ALDH) enzymatic activity identifies ovarian cancer stem-like cells. We investigated the antineoplastic activity of the ALDH inhibitor Disulfiram on bulk ovarian cancer cells and CD133+/ALDH+ cancer stem-like cells. Study Design: Ovarian cancer cell lines, human ovarian surface epithelial cells, and mesenchymal stem cells were treated with increasing concentrations of Disulfiram and/or Cisplatin in vitro. Treated cells were assessed for viability or FACS-analyzed for either percentage of ovarian cancer stem-like cells or induction of apoptosis. Disulfiram’s impact on cancer stem-like cells was tested in vitro using tumor sphere formation assays and in vivo using tumor initiation assays with in vitro-treated A2780 cells in NSG mice. Finally, Disulfiram’s in vivo activity was assessed versus CD133+/ALDH+ cell-initiated tumor xenografts. Results: Disulfiram demonstrated antineoplastic activity against multiple ovarian cancer cell lines. While Disulfiram had limited in vitro toxicity against human ovarian surface epithelial cells or mesenchymal stem cells (IC50 of ~15 μM and >30 μM, respectively), its antineoplastic activity against cell lines was comparable to Cisplatin (IC50 ~1.5 μM). Disulfiram-mediated cell death was due, at least in part, to induction of apoptosis. Disulfiram activity was additive with chemotherapy. Disulfiram demonstrated selective depletion of CD44+ cells but not the CD133+ cancer stem-like cells. Disulfiram had no therapeutic impact on tumor initiation studies or in vivo therapy of whole cell line or stem cell-initiated tumor xenografts. Conclusions: In biologically relevant concentrations, Disulfiram has clear antineoplastic activity against ovarian cancer cells in vitro. Disulfiram selectively depleted CD44+ but not CD133+ ovarian cancer stem-like cells in vitro. However, Disulfiram had no significant activity in vivo. Thus, improved and more selective ALDH inhibitors may be required to target ovarian cancer stem cells.

Toxicological Evaluation of Disulfiram, Copper Gluconate and Disulfiram/Copper Gluconate Combination on Renal Function in Rodents

This research work investigated and compared the chronic renal toxicological profile of disulfiram, copper gluconate and disulfiram/copper gluconate combination, in a 90-day time- and dose-dependent study in rodents. 88 rats weighing an average of 280 g divided into eleven groups consisting of 8 rats each were used for this experiment. The control groups received normal saline as placebo and 99.5% dimethyl sulfoxide (DMSO) (solvent control). Three oral doses (low, medium and high) of disulfiram (18.65 mg/kg, 37.3 mg/kg and 74.6 mg/kg), copper gluconate (3.75 mg/kg, 7.5 mg/kg and 15 mg/kg) and both drugs in combination were administered daily with those of the combination given 12 hours apart. Blood samples were collected via cardiac puncture in heparinised bottles and centrifuged, and the serum was decanted on 30, 45, 60 and 90 days for analysis. Renal function parameters—electrolytes (Na+, K+), urea and creatinine were evaluated. Results showed significant (p < 0.05) dose- and time-dependent increase in electrolyte level (Na+, K+), blood urea and creatinine respectively. The results are all pointers to the development of renal failure. It therefore appears that the DSF/CG combination is nephrotoxic and this effect is dose-dependent and synergistic.

Effect of Disulfiram/Copper Gluconate Combination on Haematological Indices in Rodents

The chronic toxicological profile of disulfiram/copper gluconate (DSF/CG) combination was investigated in a 90 day time and dose dependent study. A total of 148 rats weighing 260 - 300 g were used for this study;60 for the pilot study and 88 for the chronic toxicity test. 88 rats divided into eleven groups consisting of 8 rats each were used for the main experiment. Groups 1 and 2 served as control groups and received normal saline as placebo and 99.5% dimethyl sulfoxide (DMSO) (Solvent control), respectively. Drugs were administered orally via a 1 ml syringe. Animals were given three doses (1/5th, 1/10th and 1/20th) of the calculated LD50 of 373 mg/kg and 75 mg/kg for disulfiram and copper gluconate respectively. Dosing was done daily with that of the combination given 12 hours apart. Blood samples were obtained via cardiac puncture on days 30, 45, 60 and 90 for analysis. Haematological parameters showed a significant (p < 0.05) dose- and time-dependent decrease in the packed cell volume, red blood cell count, white blood cell count and platelet count respectively. The results indicate bone marrow depression evidenced by anemia, leucopenia and thrombocytopenia in the experimental animals. The DSF/CG combination appears to exhibit a synergistic dose-dependent haematotoxicity.

Disulfiram (Antabuse) Neurotoxicity: Implications of Painful Small Fiber Sensory Polyneuropathy for Lyme Disease and Addiction

This article describes the prototypical clinical presentation, electrodiagnostic and neuropathological findings and treatment of a patient with painful peripheral neuropathy due to disulfiram toxicity. Although a review of the literature fails to reveal cases of painful peripheral neuropathy due to disulfiram toxicity, there has been heightened publicity of its risk in the treatment of persistent symptoms of Lyme disease following a standard of care course of antibiotics known as post-treatment Lyme disease syndrome. This article reviews the etiopathogenesis and diagnosis of predominant small fiber neuropathy resulting from disulfiram neurotoxicity, and offers recommendations for its use in Lyme disease and alcoholism.

Adverse hepatic reactions associated with calcium carbimide and disulfiram therapy: Is there still a role for these drugs?

四乙秋兰姆化二硫和钙 carbimide 是二白酒威慑然而，广泛地在那里在酒精中毒治疗使用的狂言存在对他们的安全的大担心。hepatotoxicity 上的报告主要与四乙秋兰姆化二硫治疗有关，被出版了。钙 carbimide 的肝毒素的潜力是很好描绘的更少。这里，我们描述与被提交到 hepatotoxicity 的一张注册表并且当规定这些混合物时，指出我们面对的限制的这个治疗学的组有关的肝损坏的四个案例。对在白酒依赖的管理的这些混合物的角色的重估清楚地被需要。

The role of interleukin-18 in glioblastoma pathology implies therapeutic potential of two old drugs-disulfiram and ritonavir

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.

Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115

STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway

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.

双硫仑作用机制及其在治疗抗肾小球基底膜型肾小球肾炎中的研究进展

双硫仑作为一种治疗慢性酒精中毒的药物在临床中广泛使用。近年来,研究者提出了双硫仑治疗癌症的具体机制,如抑制乙醛脱氢酶(acetaldehyde dehydrogenase,ALDH)的活性、提高细胞内活性氧(reactive oxygen species,ROS)的浓度、抑制核因子kappa-B(nuclear factor kappa-B,NF-κB)的活性,促进与核蛋白定位蛋白4(nuclear protein localization protein 4,NPL4)的结合、抑制FROUNT蛋白等,并在多种癌症模型中证明了双硫仑的抗癌活性。抗肾小球基底膜型肾小球肾炎是急进性肾小球肾炎中的一种类型,该病一旦被确诊,就需要第一时间给予治疗,尽量帮助患者缓解症状、改善预后。研究表明,双硫仑可通过抑制C-C趋化因子受体2型/C-C趋化因子受体5型(C-C chemokine receptor type 2/C-C chemokine receptor type 5,CCR-2/CCR-5)和FROUNT蛋白之间的相互作用来抑制巨噬细胞的迁移、聚集、活化来缓解抗肾小球基底膜型肾小球肾炎,这表明双硫仑对该类患者具有潜在的治疗价值。本文简要回顾了双硫仑最新研究中阐明的相关作用分子机制,展望了未来双硫仑作为新的药物治疗抗肾小球基底膜型肾小球肾炎的前景。

双硫仑联合紫杉醇对食管癌细胞增殖、侵袭能力的抑制作用及其机制

目的探讨双硫仑联合紫杉醇对食管癌细胞增殖、侵袭能力的抑制作用并分析其机制。方法以不同浓度双硫仑(0、10、20、40μmol/L)分别作用于食管癌细胞株TE-1和TE-10,CCK-8法测算细胞活力,筛选得到双硫仑最佳作用浓度为20μmol/L。将TE-1、TE-10食管癌细胞分别分为对照组(不加药物正常培养)、双硫仑组(20μmol/L双硫仑)、紫杉醇组(0.5μmol/L紫杉醇)、双硫仑+紫杉醇组(20μmol/L双硫仑+0.5μmol/L紫杉醇)。采用MTT法观察细胞增殖能力,流式细胞术观察细胞凋亡率,Transwell实验观察细胞侵袭能力,RT-qPCR法检测细胞α微管蛋白mRNA,Western blotting法检测细胞α微管蛋白、Bcl-2蛋白。结果TE-1及TE-10细胞增殖率对照组>双硫仑组>紫杉醇组>双硫仑+紫杉醇组,TE-1及TE-10细胞凋亡率对照组<双硫仑组<紫杉醇组<双硫仑+紫杉醇组(P均<0.05),TE-1及TE-10细胞穿膜细胞数对照组>双硫仑组>紫杉醇组>双硫仑+紫杉醇组(P均<0.05)。TE-1细胞α微管蛋白mRNA表达对照组>双硫仑组>紫杉醇组>双硫仑+紫杉醇组,TE-10细胞α微管蛋白mRNA表达对照组>双硫仑组>紫杉醇组、双硫仑+紫杉醇组;TE-1及TE-10细胞α微管蛋白、Bcl-2蛋白表达对照组>双硫仑组>紫杉醇组>双硫仑+紫杉醇组(P均<0.05)。结论双硫仑联合紫杉醇可增强对食管癌细胞增殖、侵袭能力的抑制作用,其机制可能与降低细胞中微管蛋白表达、促进细胞凋亡有关。

7种常见易发生不良反应真菌的毒性分析及安全应用

目的综述见手青类、胶陀螺、黑木耳、鹅膏菌类、橘黄裸伞、毛头鬼伞、卷边桩菇7种常见易发生不良反应条件性真菌研究现状,对其毒性成分进行分析,提出相应的安全应用建议,为资源开发及可持续应用提供参考。方法通过查阅国内外文献及相关书籍,对7种常见易发生不良反应真菌的研究现状、功效作用、毒性成分、不良反应等进行总结。结果7种常见易发生不良反应真菌所含的毒性成分种类复杂,包括多肽、生物碱、氨基酸、低聚异戊二烯类等化合物,可能会引起神经毒性、光敏毒性、胃肠道刺激、双硫仑样反应、溶血性中毒等不良反应,需引起重视。同时,这些真菌富含多种生物活性成分,具有显著药理活性,部分毒性成分又具开发成抗炎、镇痛、抗抑郁等药的潜力,值得更深入研究及合理开发应用。结论易发生不良反应真菌亦是重要的药用真菌资源,极具开发价值,目前许多易发生不良反应真菌研究重点多偏重药理作用和毒理作用,其毒力因子及其中毒机制尚未明确,需进一步深入研究,为其开发应用提供参考。

毛头鬼伞的本草考证及不良反应研究进展

目的探究药用真菌毛头鬼伞的用药历史与现代研究进展,为毛头鬼伞进一步研究应用提供参考。方法查阅古代本草专著,对毛头鬼伞的名称、产地、形态、药性、功效进行考证,并结合现代文献研究进行深入探索。结果毛头鬼伞用药历史悠久,其古代名称为鬼盖、地盖、鬼屋等,现代称毛头鬼伞、鸡腿菇。性平、味甘,归胃、心经,主治小儿寒热惊痫证、疔疮肿毒、恶疮、蜈蚣蛇蝎伤。现代药理学研究表明毛头鬼伞具有抗氧化、抗癌、保护肝脏、抗炎、抗糖尿病、抗菌、抗病毒和抗线虫活性等药理作用。通过系统查阅古今文献发现,毛头鬼伞可能引起双硫仑样反应、胃肠炎型中毒、特应性皮炎患者的皮肤反应、富集重金属等不良反应。结论通过对毛头鬼伞的本草考证及不良反应进行总结,可为毛头鬼伞的安全利用提供依据。

In situ triggering antitumor efficacy of alcoholabuse drug disulfiram through Cu-based metalorganic framework nanoparticles

Although approved as an alcohol-abuse drug,disulfiram(DSF)exhibited potential anticancer activity when chelated with copper(Cu).However,the low level of intrinsic Cu,toxicity originated from exogenous Cu supplementation,and poor stability of DSF in vivo severely limited its application in cancer treatment.Herein,we proposed an in situ DSF antitumor efficacy triggered system,taking advantages of Cu-based metal-organic framework(MOF).In detail,DSF was encapsulated into Cu-MOF nanoparticles(NPs)during its formation,and the obtained NPs were coated with hyaluronic acid to enhance the tumor targetability and biocompatibility.Notably,DSF loaded Cu-MOF NPs maintained stability and integrity without Cu;leakage in blood circulation,thus showing excellent biosafety.Once accumulating at tumor site,NPs were internalized into tumor cells via receptor-mediated endocytosis and released DSF and Cu;simultaneously in the hyaluronidase-enriched and acidic intracellular tumor microenvironment.This profile lead to in situ chelation reaction between DSF and Cu;,generating toxic DSF/Cu complex against tumor cells.Both in vitro and in vivo results demonstrated the programmed degradation and recombination property of Cu-based MOF NPs,which facilitated the tumor-specific chemotherapeutic effects of DSF.This system provided a promising strategy for the application of DSF in tumor therapy.

Tumor-responsive copper-activated disulfiram for synergetic nanocatalytic tumor therapy

Exploring alternative biomedical use of traditional drugs in different disease models is highly important as it can reduce the cost of drug development and overcome several critical issues of traditional chemodrugs such as low chemotherapeutic efficiency,severe side effect,and drug resistance.Disulfiram(DSF),a clinically approved alcohol-aversion drug,was recently demonstrated tofeature tumor-growth suppression effect along with the co-administration of Cu^(2+)species,but direct Cu^(2+)administration mode might cause severe toxicity originating from low Cu^(2+)accumulation into the tumor and nonspecific Cu^(2+)distribution-induced cytotoxicity.Based on the intriguing drug-delivery performance of nanoscale metal-organic frameworks(MOFs),we herein construct HKUST nMOFs as the Cu^(2+)self-supplying nanocarriers for efficient delivery of the D SF drug.The mildly acidic condition of tumor microenvironment initially triggered the release of Cu ions from HKUST nMOFs,which further reacted with the encapsulated DSF toform toxic Cu(DDTC)2(activation)for tumor chemotherapy.Especially,during the Cu(DDTC)2 complexation,Cu^(+)species were formed concomitantly,triggering the intratumoral nanocatalytic therapy for the generation of reactive oxygen species to synergistically destroying the tumor cells/tissue.As a result,synergetic tumor-responsive chemotherapy and nanocatalytic therapy are enabled by DSF@HKU ST nanodrugs,as demonstrated by the dominant anticancer efficacy with satisfied biocompatibility both in vitro and in vivo.The present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.

Disulfiram, an aldehyde dehydrogenase inhibitor, works as a potent drug against sepsis and cancer via NETosis, pyroptosis, apoptosis, ferroptosis, and cuproptosis

Regulated cell death(RCD)is essential for maintaining cell homeostasis and preventing diseases.Besides classical apoptosis,several novel nonapoptotic forms of RCD including NETosis,pyroptosis,ferroptosis,and cuproptosis have been reported and are increasingly being implicated in various cancers and inflammation.Disulfiram(DSF),an aldehyde dehydrogenase inhibitor,has been used clinically for decades as an anti-alcoholic drug.New studies have shown that DSF possesses potent anti-inflammatory and anti-cancer effects by regulating these new types of RCD.Here,we summarize the mechanisms and discuss the potential application of DSF in the treatment of cancers and inflammatory diseases.