Institute of Clinical Medicine, University of Tartu, L. Puusepa 8, 50406, Tartu, Estonia.
Institute of Chemistry, University of Tartu, Tartu, Estonia.
Sci Rep. 2021 Oct 13;11(1):20338. doi: 10.1038/s41598-021-99630-0.
Despite the use of multimodal treatment combinations, the prognosis of glioblastoma (GB) is still poor. To prevent rapid tumor recurrence, targeted strategies for the treatment of GB are widely sought. Here, we compared the efficacy of focused modulation of a set of signaling pathways in two GB cell lines, U-251 MG and T98-G, using a panel of thirteen compounds targeting cell cycle progression, proliferation, epigenetic modifications, and DNA repair mechanism. In parallel, we tested combinations of these compounds with temozolomide and lomustine, the standard chemotherapy agents used in GB treatment. Two major trends were found: within individual compounds, the lowest IC values were exhibited by the Aurora kinase inhibitors, whereas in the case of mixtures, the addition of DNA methyltransferase 1 inhibitor azacytidine to lomustine proved the most beneficial. The efficacy of cell cycle-targeting compounds was further augmented by combination with radiation therapy using two different treatment regimes. The potency of azacytidine and lomustine mixtures was validated using a unique assay pipeline that utilizes automated imaging and machine learning-based data analysis algorithm for assessment of cell number and DNA damage extent. Based on our results, the combination of azacytidine and lomustine should be tested in GB clinical trials.
尽管采用了多种治疗方法相结合，胶质母细胞瘤（GB）的预后仍然很差。为了防止肿瘤迅速复发，人们广泛寻求针对 GB 的靶向治疗策略。在这里，我们使用针对细胞周期进程、增殖、表观遗传修饰和 DNA 修复机制的 13 种化合物组合，比较了两种 GB 细胞系 U-251 MG 和 T98-G 中一组信号通路的聚焦调节的效果。同时，我们还测试了这些化合物与替莫唑胺和顺铂（用于治疗 GB 的标准化疗药物）联合使用的组合。发现了两个主要趋势：在单个化合物中，最低的 IC 值是由 Aurora 激酶抑制剂表现出来的，而在混合物的情况下，将 DNA 甲基转移酶 1 抑制剂阿扎胞苷添加到顺铂中被证明是最有益的。通过使用两种不同的治疗方案联合放射治疗，进一步增强了细胞周期靶向化合物的功效。使用独特的检测管道验证了阿扎胞苷和顺铂混合物的效力，该检测管道利用自动化成像和基于机器学习的数据分析算法评估细胞数量和 DNA 损伤程度。基于我们的结果，阿扎胞苷和顺铂的组合应该在 GB 临床试验中进行测试。
