GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models.
GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models.
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DOI：
10.3390/cancers13235939
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发表时间：
2021-11-25
期刊：
影响因子：
5.2
通讯作者：
Short SC
中科院分区：
文献类型：
--
作者：
Brüning-Richardson A;Shaw GC;Tams D;Brend T;Sanganee H;Barry ST;Hamm G;Goodwin RJA;Swales JG;King H;Steele L;Morton R;Widyadari A;Ward TA;Esteves F;Boissinot M;Mavria G;Droop A;Lawler SE;Short SC
高级别胶质瘤仍然是难以治疗的癌症。新的治疗选择包括靶向糖原合成酶激酶3（GSK-3）诱导细胞死亡，但药物活性的模式仍然未知，与常规治疗（包括放疗）的组合尚未探索。在这里，我们描述了在体外和体内胶质瘤模型中用抑制剂AZD 2858靶向GSK-3的效果。我们确定AZD 2858暴露诱导有丝分裂缺陷，导致患者源性胶质瘤细胞系的细胞死亡和胶质瘤异种移植物的肿瘤生长延迟。联合给药也增强了放射治疗的效果。因此，我们建议AZD 2858作为高级别胶质瘤放疗的辅助治疗。背景资料：先前关于癌症模型中糖原合成酶激酶3（GSK-3）抑制的数据支持与正常组织相比对肿瘤细胞具有选择性的细胞毒性作用，但是这些抑制剂在胶质瘤中的作用尚未被广泛研究。在这里，我们调查他们的潜力，神经胶质瘤的细胞毒性。研究方法：我们使用细胞毒性试验以及对细胞周期、有丝分裂和中心体生物学影响的详细研究，评估了药理学GSK-3抑制对已建立（U87、U251）和患者来源（GBM 1、GBM 4）胶质母细胞瘤（GBM）细胞系的影响。我们还在异种移植模型中评估了单独和与放射组合的GSK-3抑制的药物摄取和功效。结果如下：使用选择性GSK-3抑制剂AZD 2858，我们在两种患者源性胶质瘤细胞系（GBM 1，GBM 4）和两种已建立的细胞系（U251和U87）中证明了单药细胞毒性，其IC 50在低微摩尔范围内促进中心体破坏，有丝分裂失败和S期阻滞。与未处理的对照相比，暴露于AZD 2858的胶质瘤异种移植物也显示出生长延迟。放射联合治疗增加了体外和原位胶质瘤异种移植物中临床放射剂量的细胞毒性作用。结论：这些数据表明，GSK-3抑制通过破坏中心体功能和促进有丝分裂失败促进胶质瘤细胞死亡，AZD 2858是临床剂量辐射的有效佐剂。
High-grade gliomas remain difficult-to-treat cancers. Novel treatment options include targeting glycogen synthase kinase 3 (GSK-3) to induce cell death but the mode of drug activity remains unknown and combination with conventional treatment including radiotherapy has not been explored. Here, we describe the effect of targeting GSK-3 with the inhibitor AZD2858 in in vitro and in vivo models of glioma. We established that AZD2858 exposure induces mitotic defects leading to cell death in patient-derived glioma cell lines and tumor growth delay in glioma xenografts. Co-administration also enhanced the effect of radiotherapy. We therefore propose AZD2858 as an adjuvant to radiotherapy in high-grade glioma. Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.
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影响因子：
11.2
作者：
Mehrara, Esmaeil;Forssell-Aronsson, Eva;Bernhardt, Peter
通讯作者：
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影响因子：
11.5
作者：
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影响因子：
10.6
作者：
Abdullah LN;Chow EK
通讯作者：
Chow EK
影响因子：
16
作者：
Jiang, W;Jimenez, G;Fukunaga, R
通讯作者：
Fukunaga, R
影响因子：
8.8
作者：
Cockle, J. V.;Picton, S.;Levesley, J.;Ilett, E.;Carcaboso, A. M.;Short, S.;Steel, L. P.;Melcher, A.;Lawler, S. E.;Bruening-Richardson, A.
通讯作者：
Bruening-Richardson, A.