Department of Neurosurgery, Xuzhou Central Hospital, 199 Jie Fang Nan Road, Xuzhou, 221009, China.
Department of Neurosurgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Zhongshan Road 321, Nanjing, 210008, China.
J Exp Clin Cancer Res. 2019 Jul 5;38(1):289. doi: 10.1186/s13046-019-1289-6.
Glioblastoma (GBM) cells with stem cell-like properties are called glioma stem cells (GSCs). GSCs display highly treatment resistance and are responsible for tumor recurrence. Napabucasin (BBI608), a novel small molecule inhibitor of STAT3, has been identified to eliminate stemness-like tumor cells in some cancers. However, the influence of Napabucasin on GBM cells, especially on GSCs, is currently unclear. In this study, we explored the influence and underlying mechanisms of Napabucasin on GBM cells.
STAT3 expression and its correlation with the glioma grade and patient survival were analyzed using CGGA and TCGA glioma databases. The influence of Napabucasin on proliferation, stemness, the cell cycle, apoptosis, and invasion of human GBM cell lines U87MG and LN229 was tested by CCK8, EdU incorporation, colony formation, Transwell invasion, and three-dimensional spheroid assays as well as flow cytometry, qPCR, and western blot analysis. The ability of Napabucasin to inhibit cell proliferation of U87MG tumor xenografts in mice was assessed using a live animal bioluminescence imaging system and immunohistochemistry.
Napabucasin suppressed the proliferation, colony formation, and invasion of U87MG and LN229 cells. Furthermore, Napabucasin induced cell cycle arrest and apoptosis. More importantly, Napabucasin treatment obviously inhibited expression of stemness-associated genes including STAT3 and suppressed the spheroid formation of glioma cells in vitro. Napabucasin also disrupted the NF-κB signaling pathway via downregulation of RelA (p65). Finally, glioma growth was effectively impaired by Napabucasin in nude mice bearing intracranial glioma xenografts.
Napabucasin treatment may be a novel approach for the treatment of GBM, particularly GSCs.
具有干细胞样特性的神经胶质瘤细胞被称为神经胶质瘤干细胞（GSCs）。GSCs 表现出高度的治疗抵抗性，是肿瘤复发的原因。Napabucasin（BBI608）是一种新型的 STAT3 小分子抑制剂，已被确定可消除某些癌症中的干性样肿瘤细胞。然而，Napabucasin 对 GBM 细胞，尤其是 GSCs 的影响目前尚不清楚。在这项研究中，我们探讨了 Napabucasin 对 GBM 细胞的影响及其潜在机制。
使用 CGGA 和 TCGA 神经胶质瘤数据库分析 STAT3 表达及其与胶质瘤分级和患者生存的相关性。通过 CCK8、EdU 掺入、集落形成、Transwell 侵袭和三维球体测定以及流式细胞术、qPCR 和 Western blot 分析检测 Napabucasin 对人 GBM 细胞系 U87MG 和 LN229 的增殖、干性、细胞周期、凋亡和侵袭的影响。使用活体动物生物发光成像系统和免疫组织化学评估 Napabucasin 抑制小鼠 U87MG 肿瘤异种移植细胞增殖的能力。
Napabucasin 抑制了 U87MG 和 LN229 细胞的增殖、集落形成和侵袭。此外，Napabucasin 诱导细胞周期停滞和细胞凋亡。更重要的是，Napabucasin 处理明显抑制了包括 STAT3 在内的干性相关基因的表达，并抑制了体外神经胶质瘤细胞球体的形成。Napabucasin 还通过下调 RelA（p65）来破坏 NF-κB 信号通路。最后，Napabucasin 在携带颅内神经胶质瘤异种移植的裸鼠中有效抑制了神经胶质瘤的生长。
Napabucasin 治疗可能是治疗 GBM，特别是 GSCs 的一种新方法。
