Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma
Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma
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DOI：
10.1038/s41598-019-46454-8
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发表时间：
2019-07-11
影响因子：
4.6
通讯作者：
Nakada, Mitsutoshi
中科院分区：
文献类型：
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作者：
Kitabayashi, Tomohiro;Dong, Yu;Nakada, Mitsutoshi
癌症干细胞与恶性肿瘤（包括胶质母细胞瘤（GBM））的化学抗性和快速复发相关。虽然替莫唑胺（TMZ）是GBM最有效的药物治疗，但GBM细胞在治疗期间获得耐药性并变得对TMZ难治。因此，胶质瘤干细胞（GSC）靶向治疗和TMZ增强治疗可能是改善GBM预后的有效方法。许多抑制维持GSC或增强TMZ效应的信号通路的药物已被报道。然而，除了目前使用的TMZ治疗外，还没有确定的治疗方法。在这项研究中，我们使用细胞活力测定筛选了由1，301种现有药物组成的药物库，以评估对GSC的影响，从而选择了kenpaullone（一种激酶抑制剂）作为靶向GSC的TMZ增强剂。Kenpaullone有效地抑制糖原合成酶激酶（GSK）3 β的活性。用kenpaullone和TMZ的组合疗法抑制GSC和胶质瘤细胞系两者的干细胞表型和活力。与TMZ单药治疗相比，小鼠模型中的联合治疗显著延长了生存时间。总之，kenpaullone是一种有前途的药物，通过靶向GSC和克服对TMZ的耐药性来治疗GBM。
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) 3 beta. 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.