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 treatment for GBM, 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 GBM prognosis. Many drugs that suppress the signaling pathways that maintain GSC or enhance the effects of TMZ have been reported. However, there are no established therapies beyond TMZ treatment currently in use. In this study, we screened drug libraries composed of 1,301 existing drugs using cell viability assays to evaluate effects on GSCs, which led to selection of kenpaullone, a kinase inhibitor, as a TMZ enhancer targeting GSCs. Kenpaullone efficiently suppressed activity of glycogen synthase kinase (GSK) 3β. Combination therapy with kenpaullone and TMZ suppressed stem cell phenotype and viability of both GSCs and glioma cell lines. Combination therapy in mouse models significantly prolonged survival time compared with TMZ monotherapy. Taken together, kenpaullone is a promising drug for treatment of GBM by targeting GSCs and overcoming chemoresistance to TMZ.
Highlights
Glioblastoma (GBM) is the most common and most malignant adult primary brain tumor
Since molecular weight of kenpaullone is low (327.18 g/mol) and kenpaullone might be highly lipophilic because of insolubility in water or ethanol and its structural formula containing two benzene rings, kenpaullone was inferred to pass through the blood brain barrier (BBB)
We previously reported that GSK3β inhibition sensitizes human GBM cell lines to TMZ through up-regulation of DNA methyltransferase 3A (DNMT3A) that methylates O-6-methylguanine methyltransferase (MGMT) promoter via c-Myc up-regulation[14]
Summary
Glioblastoma (GBM) is the most common and most malignant adult primary brain tumor. Despite development of surgical techniques and several anti-cancer drugs, GBM prognosis is still poor. One of the hypothesized causes of drug resistance and short interval of recurrence of several cancer types is the existence of cancer stem cells. It is important to establish new therapies targeting GSCs. As there are no drugs beyond TMZ for GBM, development of strategies for enhancing the effect of TMZ to overcome drug resistance and improve survival time is essential. To reduce cost and improve success rates, the concept of “drug repositioning” or “drug repurposing” has gained attention as an approach to drug discovery This concept refers to identification of new indications for already approved drugs and offers the benefits reducing costs and decreasing time required to get the drug approved[7]. We identified the drug kenpaullone, an inhibitor of glycogen synthase kinase (GSK) 3β10,11
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