Abstract
Cancer stem cells are associated with chemoresistance and rapid recurrence of malignant tumors including glioblastoma (GBM). Although temozolomide (TMZ) is the most effective drug against GBM to date, GBM cells acquire resistance and become refractory to TMZ during treatment. Therefore, glioma stem cell (GSC)-targeted therapy and TMZ enhancing therapy may be effective approaches to improve prognosis of GBM. Many drugs that suppress the signaling pathway related to maintain GSC or enhance the effect of TMZ have been reported. However, there are no established therapies. Here, we screened drug libraries that are composed of 1,301 existing drugs using cell viability assay using GSCs, then extracted Kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK)3β. Combination therapy of Kenpaullone and TMZ demonstrated suppression of stem cell properties and proliferation of both GSCs and glioma cell lines. Combination therapy for the mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, Kenpaullone is a promising drug for the treatment of GBM by targeting GSCs and overcoming chemoresistance against TMZ.