依沙佐匹克隆在体外诱导 C6 神经胶质瘤细胞凋亡和细胞周期停滞，并在颅内大鼠模型中抑制肿瘤生长。
Eslicarbazepine induces apoptosis and cell cycle arrest in C6 glioma cells in vitro and suppresses tumor growth in an intracranial rat model.
机构信息
Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, 14115-111, Iran.
Biochemical Neuroendocrinology, Division of Experimental Medicine, Faculty of Medicine and Health Sciences, Institut de Recherches Cliniques de Montréal (IRCM), McGill University, Montréal, H2W 1R7, Canada.
出版信息
BMC Cancer. 2024 Sep 4;24(1):1099. doi: 10.1186/s12885-024-12840-3.
BACKGROUND
Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects.
METHODS
To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI.
RESULTS
The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01).
CONCLUSIONS
Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma.
背景
多形性胶质母细胞瘤（GBM）是最恶性的脑肿瘤，诊断后预期寿命为 14-16 个月。GBM 的标准治疗包括手术、放疗和替莫唑胺化疗。大多数患者在一段时间后会产生耐药性，肿瘤会复发。因此，需要新的药物来治疗 GBM。依佐加滨（ESL）是一种知名的苯并二氮䓬类抗癫痫药物，具有抗癌潜力。在这项研究中，我们首次评估了 ESL 对 C6 细胞体外和体内生长的潜在影响，并研究了其分子作用。
方法
为了确定 ESL 对 C6 细胞系的影响，通过 MTT 测定、集落形成和划痕愈合试验评估 ESL 对 C6 细胞活力、增殖和迁移的影响。此外，通过流式细胞术、qRT-PCR 和 Western blot 检测细胞凋亡和细胞周期。此外，还在 Wistar 大鼠颅内模型中研究了 ESL 的体内作用，并通过卡尺和 MRI 测量肿瘤大小。
结果
所得结果极为一致且极具鼓舞性。细胞基础检测结果表明，ESL 处理的 C6 细胞活力、增殖和迁移显著受到抑制（p<0.001）。流式细胞术检测结果表明，ESL 处理导致细胞凋亡显著增强（p<0.01），并上调了细胞凋亡相关基因，如 RNA 水平（p<0.05）和蛋白水平（5.37 倍）的 Bax/Bcl2 比值。ESL 处理细胞的流式细胞分析显示 G2/M 期细胞周期阻滞。ESL 处理细胞的 p21 上调 2.49 倍，cyclin B1 下调 0.22 倍，cyclin-dependent kinase-1 下调 0.34 倍，蛋白水平下调。ESL（30mg/kg）给药也抑制了雄性大鼠颅内 C6 肿瘤的肿瘤体积和重量（p<0.01）。
结论
基于这些新发现，ESL 有可能进一步在胶质母细胞瘤的实验和临床研究中进行探索。
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