没食子酸通过活性氧介导的PI3K/AKT通路逆转胶质母细胞瘤化疗耐药的作用机制研究

Glioblastoma is the most common intracranial primary malignant tumor in adults. This fatal disease is characterized by high heterogeneity, traditional treatment resistance, and poor prognosis. Chemosensitizers for recurrent glioblastoma can effectively improve the treatment effect of recurrent tumors. Previous studies have found that reactive oxygen species significantly increased in recurrent glioblastoma, and gallic acid shows strong anti-oxidative capacity and low cytotoxicity. Therefore, we speculated that the application of gallic acid can increase the sensitivity of glioblastoma to temozolomide by inhibiting active oxygen metabolism. This study is to explore the mechanism by which gallic acid reverses the chemotherapy sensitivity of glioblastoma TMZ by multi-period transcriptome sequencing of gallic acid -treated tumors. In vitro experiments were performed to verify the signal transduction pathways related to gallic acid treatment. The efficacy and safety of gallic acid in the treatment of chemotherapy-resistant gliomas were confirmed by in vivo experiments. This study not only reveals the mechanism of gallic acid in glioma treatment, but also provides an effective adjuvant therapy for the clinical treatment of recurrent glioblastoma.

胶质母细胞瘤是成人最常见的原发性颅内恶性肿瘤，肿瘤异质性强，即使行积极治疗后，仍极易复发，复发肿瘤生长迅速，对传统化疗药物耐药，临床预后极差。筛选出复发胶质母细胞瘤的化疗增敏剂能够有效提升复发肿瘤的治疗效果。前期研究发现复发胶质母细胞瘤活性氧代谢显著增强，中药提取物没食子酸具有较强的氧化清除功效和较弱的细胞毒性。因此我们推测应用没食子酸能够通过抑制活性氧代谢提升胶质母细胞瘤对替莫唑胺的敏感性。本研究拟通过对没食子酸处理后的肿瘤细胞进行多时段转录组测序，明确其对肿瘤细胞的动态影响，并初步探索药物作用机制。通过分子生物学实验，证实没食子酸通过抑制活性氧介导的PI3K/AKT通路逆转肿瘤对替莫唑胺耐药的作用机制。通过动物成瘤模型验证没食子酸对耐药胶质母细胞瘤治疗的安全性及有效性。本研究不仅揭示了没食子酸的作用机制，并且为复发胶质母细胞瘤的临床治疗提供有效的辅助治疗手段。

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