https://orcid.org/0000-0002-3608-6219
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ABSTRACT
Introduction
Glioblastoma (GB) is one of the most challenging central nervous system (CNS) tumors in treatment options and response, urging the development of novel management strategies. The anti-alcoholism drug, disulfiram (DS), has a potential anticancer activity, and its complex mechanism of action is assumed to be well exploited against the heterogeneous GB.
Area covered
Through a systematic literature review about repositioning DS to GB treatment, an evaluation of the clinical, pharmacological, and formulation strategies is provided to specify the challenges of drug delivery and thus to advance its clinical translation. From six databases, 35 articles were selected, including case report (1); clinical trials (3); original articles mainly representing in vitro and preclinical pharmacological data, and 10 dealing with technological approaches.
Expert opinion
The repositioning of DS in GB treatment is facing drug and tumor-associated limitations due to the oral drug’s low bioavailability, unwanted metabolism, and inefficient delivery to brain-tumor tissue. Development strategies using molecular encapsulation of DS and the parenteral dosage forms improve the anticancer pharmacology of the drug. The development of optimized drug delivery systems (DDS) shows promise for the clinical translation of DS into GB adjuvant therapy.
Graphical abstract
Article highlights
Clinical relevancy of repositioning disulfiram for glioblastoma treatment
Diverse anti-glioblastoma mechanism of disulfiram
Pharmacokinetics and bioavailability of disulfiram in tumor treatment
Formulation strategies of disulfiram to overcome delivery limitations to the brain
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
List of abbreviations
| ALDH | = | aldehyde dehydrogenase |
| BCS | = | Biopharmaceutical Classification System |
| BBB | = | blood-brain barrier |
| CNS | = | central nervous system |
| CSC | = | cancer stem cells |
| Cu | = | copper |
| Cu(DDC)2 | = | bis(diethyldithiocarbamate)-copper |
| CUSP9 | = | Coordinated Undermining of Survival Paths with 9 repurposed non-oncological drugs |
| Cys | = | cysteine |
| DDC | = | diethyldithiocarbamate |
| DDS | = | drug delivery system |
| DS | = | disulfiram |
| EGFR | = | endothelial growth factor receptor |
| GB | = | glioblastoma |
| GSC | = | glioma stem cells |
| IDH | = | isocitrate dehydrogenase |
| MGMT | = | O6-methylguanine-DNA-methyltransferase |
| NF-κB | = | nuclear factor-kappa B |
| NP | = | nanoparticles |
| OS | = | overall survival |
| PD | = | pharmacodynamics |
| PFS | = | progression free survival |
| PK | = | pharmacokinetics |
| PLGA | = | poly (lactic-co-glycolic acid) |
| PRISMA | = | Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
| ROS | = | reactive oxygen species |
| RT | = | radiotherapy |
| TERT | = | telomerase reverse transcriptase |
| TIME | = | tumor immune-microenvironment |
| TMZ | = | temozolomide |
| WHO | = | World Health Organization |
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425247.2023.2190581