Glioblastoma stem cells after treatment with sulconazole.

Glioblastoma (GBM) is a uniformly lethal disease that is driven by GBM stem cells (GSCs). However, methods that selectively eradicate the GSCs remain limited. Here, we employed a chemical biology approach to identify novel compounds and strategies that target GSC proliferation, invasiveness and stemness. We studied the effect of sulconazole (SN) previously reportedly known as an antifungal drug. In GSCs SN inhibited multiple biotin-dependent carboxylases by competing with biotin, an important co-factor for these enzymes. Consequently, there was reduced carbon flux into the cholesterol biosynthesis and TCA cycle pathways, depleting intracellular cholesterol and impairing oxidative phosphorylation, resulting in impaired GSC proliferation. Notably, these metabolic changes were GSC-specific and undetected in SN treated mouse astrocytes. Thus, the pharmacologic inhibition of biotin-dependent carboxylases represents a viable therapy for GBM. Overall design: RNA-seq from glioblastoma stem cell specimens (TS-543) following treatment ether with DMSO or sulconazole nitrate.