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 Y-box 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."