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disulfiram:A novel repurposed drug for cancer therapy

Chinese Medical Journal 2024年第12期137卷 1389-1398页

作者： Min Zeng Baibei Wu Wenjie Wei Zihan Jiang Peiqiang Li Yuanting Quan Xiaobo Hu Department of Biochemistry and Molecular Biology School of Basic MedicineHengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China The Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education Hengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China Institute of Biochemistry of Hengyang Medical School University of South ChinaHengyangHunan 421001China

Cancer is a major global health *** therapeutic strategies can prolong patients’survival and reduce the costs of *** repurposing,which identifies new therapeutic uses for approved drugs,is a promising approach with the advantages of reducing research costs,shortening development time,and increasing efficiency and ***(DSF),a Food and Drug Administration(FDA)-approved drug used to treat chronic alcoholism,has a great potential as an anticancer drug by targeting diverse human *** studies show the antitumor effects of DSF,particularly the combination of DSF and copper(DSF/Cu),on a wide range of cancers such as glioblastoma(GBM),breast cancer,liver cancer,pancreatic cancer,and *** this review,we summarize the antitumor mechanisms of DSF/Cu,including induction of intracellular reactive oxygen species(ROS)and various cell death signaling pathways,and inhibition of proteasome activity,as well as inhibition of nuclear factor-kappa B(NF-κB)***,we highlight the ability of DSF/Cu to target cancer stem cells(CSCs),which provides a new approach to prevent tumor recurrence and ***,DSF/Cu inhibits several molecular targets associated with drug resistance,and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant *** of DSF/Cu may shed light on its improved application to clinical tumor treatment.

关键词： disulfiram Aldehyde dehydrogenase Reactive oxygen species Proteasome activity Cancer stem cells Drug resistance

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

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Cellular & Molecular Immunology 2024年第3期21卷 275-291页

作者： Zhi-Dong Zhang Chang-Rui Shi Fang-Xu Li Hu Gan Yanhong Wei Qianhui Zhang Xin Shuai Min Chen Yu-Lin Lin Tian-Chen Xiong Xiaoqi Chen Bo Zhong Dandan Lin Department of Gastrointestinal Surgery Medical Research InstituteFrontier Science Center of Immunology and MetabolismZhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan430071China Department of Virology College of Life SciencesWuhan UniversityWuhan430072China TaiKang Center for Life and Medical Sciences Wuhan UniversityWuhan430071China Wuhan Research Center for Infectious Diseases and Cancer Chinese Academy of Medical SciencesWuhan430071China Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan430071China Cancer Center Renmin Hospital of Wuhan UniversityWuhan430060China

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 ***,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 *** 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 ***,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^(–/–)***,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 *** 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.

关键词： STING/MITA disulfiram RNF115 SLE Autoimmunity

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Repurposing disulfiram with CuET nanocrystals:Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2698-2715页

作者： Xueming Xu Yuanfeng Han Jiali Deng Shengfeng Wang Shijie Zhuo Kai Zhao Wenhu Zhou Hematology and Department of Critical Care Medicine The Third Xiangya HospitalCentral South UniversityChangsha 410013China Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Hunan Chidren's Hospital Changsha 410007China Department of Pharmacy The Third Xiangya HospitalCentral South UniversityChangsha 410013China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing ***,disulfiram(DSF),a drug primarily used for alcohol addiction treatment,has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis,a form of programmed cell *** therapeutic activity of DSF can be further enhanced by the presence of Cu^(2+),although the underlying mechanism of this enhancement remains *** this study,we investigated the mechanistic basis of Cu^(2+)-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate(CuET)*** exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of ***,despite its potent activity,CuET suffered from poor solubility and limited permeability,as revealed by our druggability *** overcome these intrinsic limitations,we developed a scalable method to prepare CuET nanocrystals(CuET NCs)using a metal coordination-driven self-assembly *** studies demonstrated that CuET NCs exhibited a 6-fold improvement in ***,CuET NCs exhibited high biodistribution in the intestine,suggesting their potential application for the treatment of inflammatory bowel diseases(IBDs).To evaluate their therapeutic efficacy in vivo,we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis *** findings highlight the discovery of CuET as a potent anti-pyroptotic agent,and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

关键词： Drug repurposing Pyroptosis Nanoparticles Bioavailability disulfiram DSS-induced colitis NLRP3 inflammasome CuET

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

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Oncology Research 2023年第3期31卷 333-343页

作者： YAPING GAN TING LIU WEIFENG FENG LIANG WANG LI LI YINGXIA NING Department of Gynaecology and Obstetrics The First Affiliated Hospital of Jinan UniversityGuangzhouChina Department of Gynaecology and Obstetrics The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Department of Anesthesiology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Guangdong Guojian Pharmaceutical Consulting Co. Ltd.GuangzhouChina Department of Galactophore Surgery The Second Affiliated Hospital of Nanchang UniversityNanchangChina

Various therapeutic strategies have been developed to overcome ovarian ***,the prognoses resulting from these strategies are still *** 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 *** these,we identified disulfiram(DSF),an old alcohol-abuse drug,as a potential inducer of cell death in ovarian ***,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 ***,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 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 ***,the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.

关键词： Ovarian cancer Drug repositioning disulfiram Apoptosis Cuproptosis

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

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Blood Science 2022年第3期4卷 152-154页

作者： Dingrui Nie Cunte Chen Yangqiu Li Chengwu Zeng Key Laboratory for Regenerative Medicine of Ministry of Education Institute of HematologySchool of MedicineJinan UniversityGuangzhouChina

Regulated cell death(RCD)is essential for maintaining cell homeostasis and preventing *** 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 ***(DSF),an aldehyde dehydrogenase inhibitor,has been used clinically for decades as an anti-alcoholic *** studies have shown that DSF possesses potent anti-inflammatory and anti-cancer effects by regulating these new types of ***,we summarize the mechanisms and discuss the potential application of DSF in the treatment of cancers and inflammatory diseases.

关键词： Apoptosis Cuproptosis disulfiram Ferroptosis Sepsis NETosis Pyroptosis

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

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Asian Journal of Pharmaceutical Sciences 2018年第6期13卷 527-535页

作者： Chunjuan Zhang Tonghua Xu Donglei Zhang Wei He Siling Wang Tongying Jiang Shenyang Pharmaceutical University He University

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.

关键词： disulfiram Solid dispersion In-situ gel Permeability Anti-cataract

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

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Nano Research 2021年第1期14卷 205-211页

作者： Hao Chen Xi Li Minfeng Huo Liying Wang Yu Chen Wei Chen Bailiang Wang School of Ophthalmology&Optometry Eye HospialWenzhou Medical UniversityWenzhou 325027China School of Life Sciences Shanghai UniversityShanghai 200444China State Key Laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai 200050China Shanghai Tenth People's Hospital Tongji University Schoo of MedicineShanghai 200072China

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 ***(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 *** 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 *** 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 ***,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/*** 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 *** present work offers a sophisticated strategy for tumor-responsive nontoxic-to-toxic therapeutic with high biocompatibility.

关键词： disulfiram metal-organic frameworks chemotherapy Fenton-like reaction tumor suppression

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A nanosystem of copper(II)-disulfiram for cancer treatment with high efficacy and few side effects

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Frontiers of Materials Science 2021年第4期15卷 553-566页

作者： Liping ZHAO Xiaoxia WANG Mingxia JIANG Xinghan WU Mogen ZHANG Xiuwen GUAN Jinlong MA Weifen ZHANG College of Pharmacy Weifang Medical UniversityWeifang 261053China Department of Pathology Weifang Medical UniversityWeifang 261053China School of Clinical Medicine Weifang Medical UniversityWeifang 261053China Collaborative Innovation Center for Target Drug Delivery System Weifang Medical UniversityWeifang 261053China Shandong Engineering Research Center for Smart Materials and Regenerative Medicine Weifang Medical UniversityWeifang 261053China

Developing chemotherapy drugs with high efficacy and few side effects has been a bottleneck problem that requires an efficient *** active cancer treatment ingredient disulfiram(DSF),inspired by the copper(II)diethyldithiocarbamate complex(CuET),can be used in a one-pot synthesis method to construct a CuET delivery nanosystem(CuET-ZIFCu@HA).Due to the high biocompatibility,targeting of CD44 overexpressed cancer cells,and acid response of zeolitic imidazolate framework(ZIF)materials of hyaluronic acid(HA),we realized that CuET-ZIFCu@HA could become an effective and highly selective cancer *** in vivo and in vitro experiments have demonstrated that CuET-ZIFCu@HA has robust anti-tumor properties without evident side *** research provided a promising strategy for DSF nanosystems that involves simple preparation and high efficacy,both of which are key to reusing DSF in cancer treatment.

关键词： disulfiram copper(II)diethyldithiocarbamate complex zeolitic imidazolate framework targeted therapy

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

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Acta Pharmaceutica Sinica B 2021年第7期11卷 2016-2030页

作者： Lin Hou Yanlong Liu Wei Liu Mervat Balash Hongling Zhang Yi Zhang Huijuan Zhang Zhenzhong Zhang Biotherapy Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China School of Pharmacy School of Pharmaceutical SciencesZhengzhou UniversityKey Laboratory of Targeting Therapy and Diagnosis for Critical DiseasesZhengzhou 450001China

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 ***,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 ***,DSF loaded Cu-MOF NPs maintained stability and integrity without Cu;leakage in blood circulation,thus showing excellent *** 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 *** profile lead to in situ chelation reaction between DSF and Cu;,generating toxic DSF/Cu complex against tumor *** 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 *** system provided a promising strategy for the application of DSF in tumor therapy.

关键词： disulfiram Copper Metal-organic framework Hyaluronic acid Lysosomal escape DSF/Cu complex In situ Antitumor therapy

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disulfiram和Venetoclax联合对急性髓系白血病的杀伤作用及机制研究

Disulfiram和Venetoclax联合对急性髓系白血病的杀伤作用及机制研...

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作者：常林林三峡大学

学位级别：硕士

研究背景:急性髓系白血病(AML)是一种侵袭性血液系统恶性肿瘤,该病在老年人群中的发病率高达19.4/10万,随着我国人口老龄化的加剧,AML发病率会进一步提高。传统AML治疗以化疗方案为主,靶向药物的开发使AML走向靶向治疗新时代。Bcl-2抑制... 详细信息

研究背景:急性髓系白血病(AML)是一种侵袭性血液系统恶性肿瘤,该病在老年人群中的发病率高达19.4/10万,随着我国人口老龄化的加剧,AML发病率会进一步提高。传统AML治疗以化疗方案为主,靶向药物的开发使AML走向靶向治疗新时代。Bcl-2抑制剂Venetoclax,因其不局限于特定突变,靶向线粒体凋亡途径,受到极大关注。但是Venetoclax单药疗效有限,在与其他化疗药物联合时效果显著,因此一般建议联合用药使得患者实现更深度的缓解。Disulfira应用于临床已有70年,近年来多项研究表明该药包括白血病等多种癌症中具有抗肿瘤活性。鉴于disulfiram和Venetoclax都具有诱导白血病细胞凋亡作用,有必要明确这两种药物是否具有协同抗AML作用,为AML靶向治疗提供新的治疗方案。目的:本研究以AML细胞系及原代细胞为研究对象,旨在探讨disulfiram及Venetoclax单药及联合应用对AML细胞活力及凋亡水平的影响,明确两药联合是否具有协同作用,进一步探讨两药协同作用机制,为AML治疗提供新治疗策略。方法:disulfiram和Venetoclax单药或联合作用于AML细胞原代细胞,Cell Titerlumi检测细胞活力,流式细胞术检测细胞凋亡,线粒体膜电位,细胞内活性氧生成,WB检测凋亡蛋白以及抗凋亡蛋蛋白表达水平;用MOLM-13-luci细胞构建CDX动物模型,验证disulfiram和Venetoclax两药联合在体内疗效。结果(1)disulfiram及Venetoclax两药对五种AML细胞系均有细胞毒性,且呈剂量依赖;(2)disulfiram和Venetoclax联合可以抑制细胞增殖,使用Compu Syn软件计算两药联合指数(CI),结果显示两药联合CIdisulfiram后细胞增殖进一步受到抑制;(5)disulfiram和Venetoclax联合会导致细胞内ROS生成增加,细胞线粒体膜电位降低,导致细胞凋亡;(6)Western blot检测表明disulfiram联合Venetoclax会使凋亡蛋白表达增加,而抗凋亡蛋白Bcl-2、Mcl-1、Bcl-x L表达降低。结论:disulfiram和Venetoclax单药对AML细胞系具有剂量依赖毒性,且disulfiram联合Venetoclax在AML细胞系及原代细胞具有协同作用,两药联合较单药细胞凋亡率进一步增强,且两药联合诱导ROS生成、降低线粒体膜电位,凋亡蛋白表达升高、抗凋亡蛋白表达降低。

关键词： disulfiram Venetoclax 急性髓系白血病(AML) 药物协同

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