5-lipoxygenase as a target to sensitize glioblastoma to temozolomide treatment via β-catenin-dependent pathway.

Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in β-catenin level and activity upon Alox5 depletion. The inhibitory effects of Alox5 can be reversed by the addition of a Wnt agonist. Additionally, the study reveals that zileuton, an Alox5 inhibitor approved for asthma treatment, significantly improves the efficacy of temozolomide in mice without causing toxicity. Combination index analysis clearly demonstrates that zileuton and temozolomide act synergistically. These findings highlight the importance of Alox5 as a critical regulator of glioblastoma sensitivity and suggest the potential repurposing of zileuton for GBM treatment.