Birinapant is a novel SMAC peptidomimetic molecule in clinical development. It suppresses the inhibitor of apoptosis proteins (IAPs) and promotes cytochrome-C/Apaf-1/caspase-9 activation to induce effective apoptosis. Because IAP inhibition has been shown to enhance the sensitivity of cancer cells to radiation, we investigated the role of birinapant in radiosensitization of glioblastoma cells in vitro and in vivo. Two glioblastoma cell lines, U-251 and U-87, were used to analyze radiosensitization in vitro with 7-AAD cell death/apoptosis and clonogenic assays. Subcutaneous flank (U-251 and U-87) and intracranial orthotopic (U-251) xenografts in nude mice were used to evaluate radiosensitization in vivo. TNF-α levels in media and serum were measured using electrochemiluminescence. Radiosensitization in vitro was more prominent for U-251 cells than for U-87 cells. In vivo, in both tumor models, significant tumor growth delay was observed with combination treatment compared to radiation alone. There was a survival benefit with combination treatment in the orthotopic U-251 model. TNF-α levels in media correlated directly with radiation dose in vitro. These findings show that birinapant can enhance the radiosensitivity of glioblastoma cell lines in cell-based assays and tumor models via radiation-induced TNF-α. Further study into the use of birinapant with radiation therapy is warranted.

Birinapant 是一种处于临床开发阶段的新型 SMAC 拟肽分子。它抑制细胞凋亡蛋白 (IAP) 抑制剂并促进细胞色素-C/Apaf-1/caspase-9 的激活以诱导有效的细胞凋亡。因为 IAP 抑制已被证明可以增强癌细胞对辐射的敏感性，我们在体外和体内研究了 birinapant 在胶质母细胞瘤细胞放射增敏中的作用。两种胶质母细胞瘤细胞系 U-251 和 U-87 用于通过 7-AAD 细胞死亡/凋亡和克隆形成试验分析体外放射增敏作用。裸鼠皮下（U-251和U-87）和颅内原位（U-251）异种移植物用于评估体内放射增敏作用. 使用电化学发光测量培养基和血清中的 TNF-α 水平。U-251 细胞的体外放射增敏作用比 U-87 细胞更显着。在体内，在两种肿瘤模型中，与单独放疗相比，联合治疗观察到显着的肿瘤生长延迟。在原位 U-251 模型中联合治疗有生存益处。培养基中的 TNF-α 水平与体外辐射剂量直接相关。这些发现表明，birinapant 可以通过辐射诱导的 TNF-α 在基于细胞的测定和肿瘤模型中增强胶质母细胞瘤细胞系的放射敏感性。需要进一步研究使用 birinapant 进行放射治疗。