LB-100, a novel Protein Phosphatase 2A (PP2A) inhibitor, sensitizes malignant meningioma cells to the therapeutic effects of radiation.
LB-100, a novel Protein Phosphatase 2A (PP2A) inhibitor, sensitizes malignant meningioma cells to the therapeutic effects of radiation.
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DOI：
10.1016/j.canlet.2017.11.035
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发表时间：
2018-02-28
期刊：
影响因子：
9.7
通讯作者：
Park DM
中科院分区：
文献类型：
--
作者：
Ho WS;Sizdahkhani S;Hao S;Song H;Seldomridge A;Tandle A;Maric D;Kramp T;Lu R;Heiss JD;Camphausen K;Gilbert MR;Zhuang Z;Park DM
非典型和间变性脑膜瘤（AAM）占所有脑膜瘤的20%。由于其复发倾向，它们与不良结局相关。虽然手术和放射（RT）是一线治疗，但尚未确定有效的系统性药物治疗。蛋白磷酸酶2A（PP 2A）是一种广泛表达的丝氨酸/苏氨酸磷酸酶，参与细胞周期调控和DNA修复。在这里，我们研究了LB-100的放射增敏作用，LB-100是一种新型的PP 2A抑制剂，作为一种新的治疗策略。使用三种人源永生化脑膜瘤细胞系IOMM-LEE、GAR和CH-157来研究LB-100在AAM中的放射增敏潜力。通过克隆形成试验、免疫荧光、细胞周期分析和蛋白表达来评估体外存活分数。LB-100与RT联合应用的抗肿瘤作用通过颅内原位异种移植小鼠模型在体内进行了验证。药理学PP 2A抑制LB-100 RT前增强脑膜瘤细胞的放射敏感性，并降低克隆形成试验中的存活分数。LB-100增加了辐射脑膜瘤细胞中的DNA双链断裂（通过γ-H2 AX测量）、有丝分裂灾难细胞死亡和G2/M细胞周期停滞。此外，LB-100还降低了STAT 3的激活及其下游蛋白的表达。在体内，LB-100和RT组合治疗与单独RT相比延长了具有异种移植物的小鼠的存活。总之，这些结果提供了令人信服的临床前数据，支持使用LB-100作为放射增敏剂治疗恶性脑膜瘤。其临床应用潜力值得进一步研究。
Atypical and anaplastic meningiomas (AAM) represent 20% of all meningiomas. They are associated with poor outcomes due to their tendency to recur. While surgery and radiation (RT) are first line therapy, no effective systemic medical treatment has been identified. Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase involved in cell cycle regulation and DNA repair. Here, we examined radiosensitizing effects of LB-100, a novel inhibitor of PP2A against AAM as a novel treatment strategy. Three human-derived immortalized meningioma cell lines, IOMM-LEE, GAR, and CH-157, were used to investigate the radio-sensitizing potential of LB-100 in AAM. Survival fraction by clonogenic assay, immunofluorescence, cell cycle analysis and protein expression were evaluated in vitro. The antitumor effects of combining LB-100 with RT were verified in vivo by using intracranial orthotopic xenograft mouse model. Pharmacologic PP2A inhibition with LB-100 prior to RT enhanced the radiosensitivity of meningioma cells and reduced survival fraction in clonogenic assays. LB-100 increased DNA double-strand breakage (measured by γ-H2AX), mitotic catastrophe cell death, and G2/M cell cycle arrest in irradiated meningioma cells. Also, LB-100 decreased activation of STAT3 and expression of its downstream proteins. In vivo, LB-100 and RT combined treatment prolonged the survival of mice with xenografts compared to RT alone. Taken together, these results provide convincing preclinical data to support the use of LB-100 as a radiosensitizing agent for treatment of malignant meningioma. Its potential for clinical application deserves further investigation.
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影响因子：
--
作者：
Ragel, Brian T.;Couldwell, William T.;Jensen, Randy L.
通讯作者：
Jensen, Randy L.
用小分子 LB100 抑制蛋白磷酸酶 2A，通过诱导有丝分裂灾难和阻断 DNA 损伤修复，使鼻咽癌异种移植物放射增敏。
影响因子：
--
作者：
Lv P;Wang Y;Ma J;Wang Z;Li JL;Hong CS;Zhuang Z;Zeng YX
通讯作者：
Zeng YX
影响因子：
15.9
作者：
Furtner, Julia;Schoepf, Veronika;Preusser, Matthias
通讯作者：
Preusser, Matthias
DOI：
10.1016/s1470-2045(12)70558-2
发表时间：
2013-05
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Perrotti D;Neviani P
通讯作者：
Neviani P
影响因子：
4.8
作者：
Aghi, Manish K.;Carter, Bob S.;Barker, Fred G., II
通讯作者：
Barker, Fred G., II