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Disulfiram in glioma: Literature review of drug repurposing.

ABSTRACT: Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.

SUBMITTER: Zhong S

PROVIDER: S-EPMC9448899 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Disulfiram in glioma: Literature review of drug repurposing.

Zhong Shiyu S Shengyu Liu Xin Shi Zhang Xudong X Li Kunhang K Liu Guojun G Li Lishuai L Tao Shanwei S Zheng Bowen B Sheng Weichen W Ye Ziyin Z Xing Qichen Q Zhai Qingqing Q Ren Lijie L Wu Ying Y Bao Yijun Y

Frontiers in pharmacology 20220824

Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have al ...[more]

PMID: 36091753

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Project description:Background: Alzheimer's disease (AD) is a debilitating neurodegenerative condition with few treatment options available. Drug repurposing studies have sought to identify existing drugs that could be repositioned to treat AD; however, the effectiveness of drug repurposing for AD remains unclear. This review systematically analyzes the progress made in drug repurposing for AD throughout the last decade, summarizing the suggested drug candidates and analyzing changes in the repurposing strategies used over time. We also examine the different types of data that have been leveraged to validate suggested drug repurposing candidates for AD, which to our knowledge has not been previous investigated, although this information may be especially useful in appraising the potential of suggested drug repurposing candidates. We ultimately hope to gain insight into the suggested drugs representing the most promising repurposing candidates for AD. Methods: We queried the PubMed database for AD drug repurposing studies published between 2012 and 2022. 124 articles were reviewed. We used RxNorm to standardize drug names across the reviewed studies, map drugs to their constituent ingredients, and identify prescribable drugs. We used the Anatomical Therapeutic Chemical (ATC) Classification System to group drugs. Results: 573 unique drugs were proposed for repurposing in AD over the last 10 years. These suggested repurposing candidates included drugs acting on the nervous system (17%), antineoplastic and immunomodulating agents (16%), and drugs acting on the cardiovascular system (12%). Clozapine, a second-generation antipsychotic medication, was the most frequently suggested repurposing candidate (N = 6). 61% (76/124) of the reviewed studies performed a validation, yet only 4% (5/124) used real-world data for validation. Conclusion: A large number of potential drug repurposing candidates for AD has accumulated over the last decade. However, among these drugs, no single drug has emerged as the top candidate, making it difficult to establish research priorities. Validation of drug repurposing hypotheses is inconsistently performed, and real-world data has been critically underutilized for validation. Given the urgent need for new AD therapies, the utility of real-world data in accelerating identification of high-priority candidates for AD repurposing warrants further investigation.

Project description: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.

Dataset Information

Disulfiram in glioma: Literature review of drug repurposing.

Publications

Disulfiram in glioma: Literature review of drug repurposing.

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