Department of Radiation Oncology, Seoul National University, Graduate School of Medicine, Seoul, Korea.
Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
Cancer Res Treat. 2016 Apr;48(2):687-97. doi: 10.4143/crt.2014.320. Epub 2015 Jun 4.
We investigated the effect of chemoradiotherapy with PP2 and temozolomide (TMZ) on malignant glioma cells using clonogenic assays and in vivo brain tumor model.
The effect of PP2 on radiosensitivity of U251 and T98G cells was investigated using clonogenic assays. The expression of E-cadherin, matrix metalloproteinases 2 (MMP2), Ephrin type-A receptor 2 (EphA2), and vascular endothelial growth factor (VEGF) was measured by Western blotting and an accumulation of γH2AX foci 6 hours after radiotherapy was measured after PP2 treatment. The effect of PP2 on migration, invasion, and vasculogenic mimicry formation (VMF) of U251 cells was evaluated. In an orthotopical brain tumor model with U251 cells, PP2 was injected intraperitoneally with or without oral TMZ before, during and after whole brain radiotherapy. Bioluminescence images were taken to visualize in vivo tumors and immunohistochemical staining of VEGF, CD31, EphA2, and hypoxia-inducible factor 1a was performed.
PP2 increased radiosensitivity of U251 and T98G cells without decreasing survival of normal human astrocytes. Chemoradiotherapy with PP2 and TMZ resulted in increased accumulation of γH2AX foci. PP2 induced overexpression of E-cadherin and suppression of MMP2, VEGF, and EphA2. PP2 also compromised invasion, migration, and VMF of U251 cells. In brain tumors, chemoradiotherapy with PP2 and TMZ decreased tumor volume best, but not statistically significantly compared with chemoradiotherapy with TMZ. The expression of VEGF and CD31 was suppressed in PP2-treated tumors.
PP2 enhances radiosensitivity of malignant glioma cells and suppresses invasion and migration of U251 cells. Chemoradiotherapy with PP2 and TMZ resulted in non-significant tumor volume decrease.
我们通过集落形成实验和体内脑肿瘤模型，研究了顺铂和替莫唑胺（TMZ）联合化学放疗对恶性神经胶质瘤细胞的影响。
通过集落形成实验，研究了 PP2 对 U251 和 T98G 细胞放射敏感性的影响。用 Western blot 检测 E-钙黏蛋白、基质金属蛋白酶 2（MMP2）、EphA2 受体 2（EphA2）和血管内皮生长因子（VEGF）的表达，并用 PP2 处理后 6 小时检测放射后 γH2AX 焦点的积累。评估 PP2 对 U251 细胞迁移、侵袭和血管生成拟态形成（VMF）的影响。在 U251 细胞的原位脑肿瘤模型中，在全脑放疗前、中、后，通过腹腔内注射和/或口服 TMZ 给予 PP2。进行生物发光成像以可视化体内肿瘤，并进行 VEGF、CD31、EphA2 和缺氧诱导因子 1a 的免疫组织化学染色。
PP2 增加了 U251 和 T98G 细胞的放射敏感性，而不降低正常人星形胶质细胞的存活率。PP2 联合 TMZ 化学放疗导致 γH2AX 焦点的积累增加。PP2 诱导 E-钙黏蛋白过表达，抑制 MMP2、VEGF 和 EphA2。PP2 还损害了 U251 细胞的侵袭、迁移和 VMF。在脑肿瘤中，PP2 联合 TMZ 化学放疗可使肿瘤体积缩小，但与 TMZ 化学放疗相比无统计学意义。PP2 处理的肿瘤中 VEGF 和 CD31 的表达受到抑制。
PP2 增强恶性神经胶质瘤细胞的放射敏感性，并抑制 U251 细胞的侵袭和迁移。PP2 联合 TMZ 化学放疗导致肿瘤体积无显著减小。
