背景:多形性胶质母细胞瘤(GBM)是最恶性的脑肿瘤,诊断后预后差,预期寿命为14-16个月。GBM的标准治疗包括手术,放射治疗,和替莫唑胺化疗。大多数患者在一段时间后变得对治疗有抵抗力,肿瘤复发.因此,需要新药来管理GBM。Esilicarbazepine(ESL)是一种众所周知的抗癫痫药物,属于具有抗癌潜力的二苯并氮卓类。在这项研究中,第一次,我们评估了ESL对C6细胞生长的潜在影响,在体外和体内,并研究了它的分子效应。
方法:为了确定ESL对c6细胞系的影响,细胞活力,扩散,通过MTT测定评估和迁移,菌落形成,和伤口愈合试验。此外,细胞凋亡和细胞周期通过流式细胞术检查,qRT-PCR,和西方印迹。此外,用Wistar大鼠颅内模型研究ESL在体内的作用,使用Caliper和MRI测量肿瘤大小。
结果:获得的结果非常一致且令人鼓舞。C6细胞活力,扩散,在ESL处理的C6细胞中,迁移被显著抑制(p<0.001),通过基于细胞的测定法确定。ESL处理导致细胞凋亡显著增强(p<0.01),通过流式细胞术确定,以及与细胞凋亡有关的基因的上调,例如RNA(p<0.05)和蛋白质水平(5.37倍)的Bax/Bcl2比率。ESL处理细胞的流式细胞术分析显示G2/M期细胞周期停滞。ESL处理的细胞显示p21上调2.49倍,在蛋白质水平上,细胞周期蛋白B1下调0.22倍,细胞周期蛋白依赖性激酶1下调0.34倍。向带有C6颅内肿瘤的雄性大鼠施用ESL(30mg/kg)也抑制了肿瘤体积和重量(p<0.01)。
结论:基于这些新发现,ESL在胶质母细胞瘤中具有进一步实验和临床研究的潜力。
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.