洛美曲昔增加 MGMT 未甲基化的人胶质母细胞瘤细胞系的放射敏感性。
Lomeguatrib Increases the Radiosensitivity of MGMT Unmethylated Human Glioblastoma Multiforme Cell Lines.
机构信息
Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Department of Radiation Oncology, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany.
出版信息
Int J Mol Sci. 2021 Jun 24;22(13):6781. doi: 10.3390/ijms22136781.
BACKGROUND
Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response.
METHODS
Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation.
RESULTS
Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM.
CONCLUSION
Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.
背景
胶质母细胞瘤对化疗和放疗的耐药性仍然是一个尚未克服的挑战。特别是，O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）启动子未甲基化的患者从替莫唑胺化疗中获益甚微，因为 MGMT 会抵消其治疗效果。因此，需要开发新的放疗治疗方案来抑制 MGMT 并提高放疗反应。
方法
洛美曲昔布是一种高度特异性的 MGMT 抑制剂，用于体外失活 MGMT 蛋白。使用集落形成存活测定法研究了洛美曲昔布联合已建立的人胶质母细胞瘤细胞系的放射敏感性。使用 Western Blot 分析抑制 MGMT。研究细胞周期分布和细胞凋亡，以确定洛美曲昔布单独以及与电离辐射联合使用的影响。
结果
洛美曲昔布显著降低了 MGMT 蛋白水平，并减少了放射诱导的 G2/M 期阻滞。当以 1 µM 给药时，观察到洛美曲昔布的放射增敏作用，而在 20 µM 时则增加了放射抗性。
结论
低浓度的洛美曲昔布引起放射增敏，而高浓度则介导放射保护作用。
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