School of Biomedical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation for Cancer Medicine, Guangzhou 510060, China.
Int J Mol Sci. 2023 Aug 2;24(15):12329. doi: 10.3390/ijms241512329.
Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells' malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity.
脑肿瘤的治疗一直具有挑战性。在这里，我们建立了一种多靶点神经分化（MTND）治疗鸡尾酒，通过针对脑癌的重要特征：细胞分化不良和细胞周期受损，来实现脑恶性肿瘤的有效和安全治疗。体外和体内实验证实了我们的 MTND 疗法具有显著的治疗效果。在临床细胞中，与目前的一线化疗药物相比，我们的治疗方法显著提高了治疗效果，对肿瘤细胞的生长和迁移有很大的抑制作用。进一步的体内实验证实，持续的 MTND 治疗可使肿瘤面积减少 73%。MTND 还诱导了与细胞周期退出/阻滞相关的表型的强烈表达，并从临床神经胶质瘤细胞快速重编程为谷氨酸能和 GABA 能表达细胞，这两种关键神经元类型涉及许多人类大脑功能，包括学习和记忆。总之，MTND 诱导了多靶点基因型表达变化，实现了神经胶质瘤细胞的直接神经转化，并控制了细胞周期/肿瘤发生的发展，有助于控制肿瘤细胞的恶性增殖，从而能够有效地、安全地治疗脑恶性肿瘤。这些令人鼓舞的结果为开发超越细胞毒性药物的脑恶性肿瘤新疗法开辟了道路，提供了更有效的药物治疗建议，同时降低了毒性。
