State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
Sci Rep. 2019 Mar 5;9(1):3462. doi: 10.1038/s41598-019-39852-5.
Glioblastoma (GBM) is the most common and aggressive malignant tumor in adult brain. Even with the current standard therapy including surgical resection followed by postoperative radiotherapy and chemotherapy with temozolomide (Temo), GBM patients still have a poor median survival. Reprogramming of tumor cells into non-malignant cells might be a promising therapeutic strategy for malignant tumors, including GBM. Based on previous studies using small molecules to reprogram astrocytes into neuronal cells, here we further identified a FTT cocktail of three commonly used drugs (Fasudil, Tranilast, and Temo) to reprogram patient-derived GBM cells, either cultured in serum containing or serum-free medium, into neuronal like cells. FTT-treated GBM cells displayed a neuronal like morphology, expressed neuronal genes, exhibited neuronal electrophysiological properties, and showed attenuated malignancy. More importantly, FTT cocktail more significantly suppressed tumor growth and prolonged survival in GBM patient derived xenograft than Temo alone. Our study provided preclinical evidence that the neuronal reprogramming drug cocktail might be a promising strategy to improve the existing treatment for GBM.
胶质母细胞瘤（GBM）是成人脑内最常见且侵袭性最强的恶性肿瘤。即使采用目前的标准治疗方法，包括手术切除后辅以替莫唑胺（Temo）的术后放疗和化疗，GBM 患者的中位生存期仍然很差。将肿瘤细胞重编程为非恶性细胞可能是一种很有前途的治疗策略，包括 GBM。基于先前使用小分子将星形胶质细胞重编程为神经元细胞的研究，我们进一步确定了三种常用药物（法舒地尔、曲尼司特和替莫唑胺）的 FTT 鸡尾酒，可将源自患者的 GBM 细胞在含血清或无血清培养基中重编程为类神经元细胞。FTT 处理的 GBM 细胞呈现出神经元样形态，表达神经元基因，表现出神经元电生理特性，并显示出恶性程度降低。更重要的是，FTT 鸡尾酒比单独使用替莫唑胺更能显著抑制 GBM 患者来源异种移植瘤的生长并延长生存期。我们的研究提供了临床前证据，表明神经元重编程药物鸡尾酒可能是改善 GBM 现有治疗方法的有前途的策略。
