Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

Yoshino, Hirofumi; Yamada, Yasuaki; Enokida, Hideki; Osako, Yoichi; Tsuruda, Masafumi; Kuroshima, Kazuki; Sakaguchi, Takashi; Sugita, Sunao; Tatarano, Shuichi; Nakagawa, Masayuki

doi:10.1371/journal.pone.0236119

Cited by 20 publications

(19 citation statements)

References 38 publications

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“…Proteasome inhibition activity of DSF was first reported by Lovborg et al (2006) by showing its specific inhibition for 26S proteasome (Lovborg et al, 2006). Combination of DSF or metabolite DDC with Cu has been shown to be a potent inhibitor of the functional proteasomes in many cancers (Kona et al, 2011;Triscott et al, 2012;Brüning and Kast, 2014;Yoshino et al, 2020). Notably, DSF/Cu was shown to inhibit the proteasome activity in breast cancer models but not in normal breast cells.…”

Section: Disulfiram and Proteasome Inhibitionmentioning

confidence: 96%

“…Reaction between DSF, DDC and Cu results in the generation of extracellular ROS, which in turn induce apoptosis in cancer cells (Lewis et al, 2014;Tawari et al, 2015). It is also demonstrated that the metabolite of DSF, DDC and its copper complex Cu(DDC) 2 get accumulated in the cancer cells and induce ROS generation leading to apoptosis in cancer cells (Guo et al, 2010;Yip et al, 2011;Tawari et al, 2015;Lu et al, 2020;Majera et al, 2020;Yoshino et al, 2020). Generation of both extracellular and intracellular ROS is completely relied on the intact thiol group which chelates copper (Figure 3).…”

Section: Disulfiram-induced Cell Deathmentioning

confidence: 99%

“…Studies from our group (Chen et al, 2006) showed that low concentrations of DSF can partially bind to the 20S proteasome molecule and inhibiting the chymotrypsin-like activity of the proteasome. It is also speculated that DSF inhibits POH1, a protein which plays an important role in deubiquitinating function of the proteasome lid rather than the actual core proteasome (Chen et al, 2006;Cvek and Dvorak, 2007;Gallery et al, 2007;Yu et al, 2007;Yoshino et al, 2020).…”

Section: Disulfiram and Proteasome Inhibitionmentioning

confidence: 99%

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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: 96%

Section: Disulfiram-induced Cell Deathmentioning

confidence: 99%

Section: Disulfiram and Proteasome Inhibitionmentioning

confidence: 99%

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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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“…If this state lasts longer, it can lead to cell cycle arrest and apoptosis induction [ 37 ]. Moreover, disulfiram offers the potential of a similar mechanism of protein degradation inhibition because, as mentioned above, the CuET complex binding NPL4 cofactor inhibits NPL4, which is involved in the p97-dependent processes, leading to protein degradation [ 53 ].…”

Section: Disulfirammentioning

confidence: 99%

Possible Therapeutic Potential of Disulfiram for Multiple Myeloma

Drozdkova

Trtková

2021

Current Oncology

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Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most probable at around 65 years of age, and the average survival of patients is estimated to be 5–10 years, specifically due to frequent relapses and resistance to the therapy used. Thus, the search for new therapeutic approaches is becoming a big challenge. Disulfiram (DSF), a substance primarily known as a medication against alcoholism, has often been mentioned in recent years in relation to cancer treatment for its secondary anti-cancer effects. Recent studies performed on myeloma cell lines confirm high inhibition of the cell growth activity if a complex of disulfiram and copper is used. Its significant potential is now being seen in the cure of haematological malignities.

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“…Here, we assessed Disulfiram (Antabuse), a well-tolerated alcohol-abuse drug and a promising candidate for repurposing in oncology [ 27 – 30 ]. In the context of MM, DSF might be particularly interesting because its anticancer activity is related to the CuET metabolite which is spontaneously formed in-vivo and in-vitro in the presence of copper ions [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment

et al. 2022

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Despite several approved therapeutic modalities, multiple myeloma (MM) remains an incurable blood malignancy and only a small fraction of patients achieves prolonged disease control. The common anti-MM treatment targets proteasome with specific inhibitors (PI). The resulting interference with protein degradation is particularly toxic to MM cells as they typically accumulate large amounts of toxic proteins. However, MM cells often acquire resistance to PIs through aberrant expression or mutations of proteasome subunits such as PSMB5, resulting in disease recurrence and further treatment failure. Here we propose CuET—a proteasome-like inhibitor agent that is spontaneously formed in-vivo and in-vitro from the approved alcohol-abuse drug disulfiram (DSF), as a readily available treatment effective against diverse resistant forms of MM. We show that CuET efficiently kills also resistant MM cells adapted to proliferate under exposure to common anti-myeloma drugs such as bortezomib and carfilzomib used as the first-line therapy, as well as to other experimental drugs targeting protein degradation upstream of the proteasome. Furthermore, CuET can overcome also the adaptation mechanism based on reduced proteasome load, another clinically relevant form of treatment resistance. Data obtained from experimental treatment-resistant cellular models of human MM are further corroborated using rather unique advanced cytotoxicity experiments on myeloma and normal blood cells obtained from fresh patient biopsies including newly diagnosed as well as relapsed and treatment-resistant MM. Overall our findings suggest that disulfiram repurposing particularly if combined with copper supplementation may offer a promising and readily available treatment option for patients suffering from relapsed and/or therapy-resistant multiple myeloma.

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Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

Cited by 20 publications

References 38 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

Possible Therapeutic Potential of Disulfiram for Multiple Myeloma

A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment

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