State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Eur J Pharmacol. 2011 Aug 1;663(1-3):9-16. doi: 10.1016/j.ejphar.2011.04.056. Epub 2011 May 17.
Topiramate has been used in patients with brain tumors who develop epilepsy. In our previous research we found topiramate could inhibit tumor metastases of Lewis lung carcinoma in C57BL/6 mice. In this study we aimed to assess the antimetastatic activity of topiramate and determine its mechanism of action. After confirming the effects of topiramate on Lewis lung carcinoma in C57BL/6 mice, we assessed the mRNA expression of carbonic anhydrases II and IX, and the vascular endothelial growth factor (VEGF) distribution in tumor tissue. We studied the role of topiramate on primary angiogenesis using a chicken embryo chorioallantoic membrane angiogenesis model, and analyzed the protein profile of serum from mice treated with or without topiramate by two-dimensional electrophoresis. We found that topiramate significantly reduced the primary tumor growth (P<0.05) and the degree of damage to the lung alveoli caused by metastatic tumor deposits. The two-dimensional electrophoresis revealed changes that occurred with topiramate treatment and four down-regulated protein spots were clearly identified as tropomyosin, osteopontin, transthyretin, and serum amyloid A-1. The mRNA and protein expression of serum amyloid A-1, osteopontin and its receptor, integrin α(v)β(3) in tumor tissue were reconfirmed. The results suggest that topiramate has antitumor and antimetastatic effects on Lewis lung carcinoma. Its mechanism of action may be related to its inhibition of angiogenesis by down-regulation of osteopontin, VEGF and carbonic anhydrase II.
托吡酯已被用于患有脑瘤并发生癫痫的患者。在我们之前的研究中发现，托吡酯可抑制 C57BL/6 小鼠Lewis 肺癌的肿瘤转移。在这项研究中，我们旨在评估托吡酯的抗转移活性，并确定其作用机制。在确认托吡酯对 C57BL/6 小鼠Lewis 肺癌的影响后，我们评估了肿瘤组织中碳酸酐酶 II 和 IX 的 mRNA 表达以及血管内皮生长因子（VEGF）的分布。我们使用鸡胚绒毛尿囊膜血管生成模型研究了托吡酯对原发性血管生成的作用，并通过二维电泳分析了用或不用托吡酯治疗的小鼠血清的蛋白质谱。我们发现托吡酯可显著降低原发性肿瘤的生长（P<0.05）以及转移瘤沉积物对肺肺泡造成的损伤程度。二维电泳显示出托吡酯治疗所引起的变化，并且四个下调的蛋白质斑点被明确鉴定为原肌球蛋白、骨桥蛋白、转甲状腺素蛋白和血清淀粉样蛋白 A-1。血清淀粉样蛋白 A-1、骨桥蛋白及其受体整合素α（v）β（3）在肿瘤组织中的 mRNA 和蛋白表达也得到了重新确认。结果表明，托吡酯对 Lewis 肺癌具有抗肿瘤和抗转移作用。其作用机制可能与其通过下调骨桥蛋白、VEGF 和碳酸酐酶 II 抑制血管生成有关。
