Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4

Ding, Nan; Zhu, Qianzheng

doi:10.21037/tcr.2018.03.33

Cited by 10 publications

(5 citation statements)

References 24 publications

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“…The main target of CuET in p97 segregase pathway is NPL4, a key component of p97 segregase. The interaction of NPL4 and CuET results in the formation of protein aggregates and immobilization of otherwise very mobile NPL4-p97 complex which triggers the cellular heat shock response and endoplasmic reticulum (ER) stress/unfolded protein response, eventually leading to cell death (Ding and Zhu, 2018;Skrott et al, 2019). CuET can also induce replication stress via NPL4 targeting.…”

Section: Disulfiram and Proteasome Inhibitionmentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

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Section: Disulfiram and Proteasome Inhibitionmentioning

confidence: 99%

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Kannappan

Ali

Small

et al. 2021

Front. Mol. Biosci.

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show abstract

“…DSF, as an anticancer agents approved by FDA, has been shown promising anticancer effects in various cancer cell lines, such as prostate cancer, breast cancer, lung cancer, leukemia, and cervical adenocarcinoma [14–16]. Here, we examined the toxicity effect of DSF on HeLa cells using CCK‐8 assay prior to investigating the antimetastatic potential of DSF.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous reports in vivo and/or in vitro have approved that DSF can regulate tumor growth through the inhibition of proteasome activity, induction of apoptosis [10], inhibition of invasion and angiogenesis [11], blockage of drug resistance [12], and suppression of stem cell‐like properties [13] in several cancer cells [14–16]. Additionally, DSF has a potential effect on suppressing DNA methylation by targeting epigenetic mechanisms [17, 18].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)

Zheng

Liu

et al. 2021

Proteomics Clinical Apps

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Purpose Disulfiram (DSF) has been proven safe and shows the promising antitumor effect in preclinical studies. However, the precise mechanism of DSF on tumor is rarely reported. This study aims to fully understand the mechanism of action of DSF with a systems perspective in anticancer effects. Experimental Design SILAC‐based quantitative proteomics strategy was used to systematically identify differential expression proteins (DEPs) after DSF treatment in HeLa cells. Bioinformatical analysis (PANTHER, DAVID, and STRING) were performed to characterize biological functions of DEPs. Functional studies were performed to explore underlying mechanisms of DSF in cancer cells. Results In total, 201 proteins were dysregulated significantly after DSF exposure. Functional studies of hexokinase 2 (HK2), which catalyzed the first irreversible enzymatic step in glucose metabolism, revealed that various phenotypic effects observed after DSF treatment in cancer cells, at least partly, through the regulation of HK2 expression. Conclusions and Clinical Relevance By correlating the proteomics data with these functional studies, the current results provided novel insights into the mechanism underlying DSF function in cancer cells. Meanwhile, these provided theoretical basis for the new use of old drugs in clinical therapy.

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“…In our screening, the disulfiram molecule stabilized the WFS1 protein. The stabilization is likely due to the inhibitory function of disulfiram on NPL4, an adaptor of p97/VCP segregase, which is essential for ER-associated degradation (ERAD) ( 63 , 64 ). ERAD is a crucial system aiming to mitigate ER stress.…”

Section: Discussionmentioning

confidence: 99%

Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome

Kitamura¹,

Maxwell²,

Ye³

et al. 2022

JCI Insight

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Conflict of interest:FU is an inventor of 3 patents related to Wolfram syndrome treatment, US 9,891,231 "Soluble MANF in pancreatic beta-cell disorders, " and US 10,441,574 and US 10,695,324 "Treatment for Wolfram syndrome and other endoplasmic reticulum stress disorders. " JRM is an inventor on a patent and patent application relating to stem cell-derived pancreatic islets, US 10,030,229 "SC-β cells and compositions and methods for generating the same" and US application PCT/US2019/032643 "Methods and Compositions for Generating Cells of Endodermal Lineage and Beta Cells and Uses Thereof. " FU is a founder and president of CURE4WOLFRAM, Inc. JRM is a consultant for Sana Biotechnology. JC and JK are co-CEOs of and report personal fees from and equity holdings in Amylyx Pharmaceuticals Inc. JC and JK have 2 patents, "Compositions for improving cell viability and methods of use thereof" (US 9,872,865; US Patent 10,251,896; AU 2014242123; EP 14775675.3; and JP2016515575A) and "For improving the composition of cell viability and using the method for the composition" (CN105050593B), issued to Amylyx Pharmaceuticals Inc. JL reports personal fees from and equity holdings in Amylyx Pharmaceuticals Inc.

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Disulfiram combats cancer via crippling valosin-containing protein/p97 segregase adaptor NPL4

Cited by 10 publications

References 24 publications

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)

Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome

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