Concise Review: Bullseye: Targeting Cancer Stem Cells to Improve the Treatment of Gliomas by Repurposing Disulfiram

Abstract

Cancer stem cells (CSCs) are thought to be at the root of cancer recurrence because they resist conventional therapies and subsequently reinitiate tumor cell growth. Thus, targeting CSCs could be the bullseye to successful cancer therapeutics in the future. Brain tumors are some of the most challenging types of cancer to treat and the median survival following the initial diagnosis is 12-18 months. Among the different types of brain tumors, glioblastoma (GBM) is considered the most aggressive and remains extremely difficult to treat. Despite surgery, radiation, and chemotherapy, most patients develop refractory disease. Temozolomide (TMZ) is a chemotherapy used to treat GBM however resistance develops in most patients. The underlying mechanisms for TMZ resistance (TMZ-resistant) involve the expression of DNA repair gene O(6)-methylguanine-DNA methyltransferase. CSC genes such as Sox-2, BMI-1, and more recently Ybox binding protein-1 also play a role in resistance. In order to develop novel therapies for GBM, libraries of small interfering RNAs and off-patent drugs have been screened. Over the past few years, several independent laboratories identified disulfiram (DSF) as an off-patent drug that kills GBM CSCs. Reportedly DSF has several modes of action including its ability to inhibit aldehyde dehydrogenases, E3 ligase, polo-like kinase 1, and NFkB. Due to the fact that GBM is a disease of heterogeneity, chemotherapy with multitargeting properties may be the way of the future. In broader terms, DSF kills CSCs from a range of different cancer types further supporting the idea of repurposing it for "target practice

Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

“…Intensive research and numerous clinical studies established disulfiram as a safe drug lacking significant side effects. More recently, an extensive spectrum of potentially exploitable bioactivities beyond its initial clinical application has established disulfiram as an attractive candidate for multiple drug repositioning efforts (11,12,(61)(62)(63). One of disulfiram's most promising traits is the ability to selectively target certain types of cancer, which is partially attributable to its ability to form a copper complex that inhibits proteasome functions (64,65).…”

“…Studies to evaluate the potency of disulfiram against certain types of cancer (12)(13)(14), Menkes disease (15), and HIV-1 infections are ongoing or have just been completed (16,17). Of additional interest to the medical community are its antinematode (18), antifungal (19), and, importantly, its antibacterial properties (11,(20)(21)(22)(23)(24).…”

Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells

“…This concept was first demonstrated in leukemia and increasing evidence supports this model in various types of solid tumors including cervical cancer (19)(20)(21)(22)(23)(24). CSCs are thought to be involved in tumor recurrence and metastasis; failure to treat CSCs by surgery or chemotherapy would result in relapse (17).…”

Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds

“…Currently, trials are underway to determine the optimal doses at which its safety profile can be maintained (hepatotoxicity has been observed at high doses), to exploit the highest tumor cell response, and to investigate its combination with other drugs (e.g., copper supplements) (Table 1), as well as the definition of its in vivo mechanism of action [49].…”