Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Mol Cancer Ther. 2010 Mar;9(3):631-41. doi: 10.1158/1535-7163.MCT-09-0652. Epub 2010 Mar 2.
Our laboratory has previously shown that a novel compound, 2,5-dimethyl-celecoxib (DMC), which is structurally similar to the cyclooxygenase-2 (COX-2) inhibitor celecoxib but lacks the COX-2-inhibitory function, mimics the antitumor effects of celecoxib. Most studies on DMC, however, focused on its effects on tumor cells. Here, we investigated the activities of DMC as an antiangiogenic agent in both in vitro and in vivo systems. Using primary cultures of human glioma specimens, we found that DMC treatment was cytotoxic to tumor-associated brain endothelial cells (TuBEC), which was mediated through the endoplasmic reticulum stress pathway. In contrast, confluent cultures of quiescent human BEC did not undergo cell death. DMC potently suppressed the proliferation and migration of the TuBEC. DMC caused no apparent effects on the secretion of vascular endothelial growth factor and interleukin-8 but inhibited the secretion of endothelin-1 in tumor-associated EC. DMC treatment of glioma xenografts in mice resulted in smaller tumors with a pronounced reduction in microvessel density compared with untreated mice. In vitro and in vivo analyses confirmed that DMC has antivascular activity. Considering that DMC targets both tumor cells and tumor-associated ECs, this agent is a promising anticancer drug.
我们的实验室之前已经表明，一种新型化合物 2,5-二甲基塞来昔布（DMC），其结构与环氧化酶-2（COX-2）抑制剂塞来昔布相似，但缺乏 COX-2 抑制功能，模拟了塞来昔布的抗肿瘤作用。然而，大多数关于 DMC 的研究都集中在其对肿瘤细胞的影响上。在这里，我们研究了 DMC 作为一种抗血管生成剂在体外和体内系统中的活性。使用人胶质瘤标本的原代培养物，我们发现 DMC 处理对肿瘤相关的脑内皮细胞（TuBEC）具有细胞毒性，这是通过内质网应激途径介导的。相比之下，静止的人 BEC 的汇合培养物不会发生细胞死亡。DMC 强烈抑制 TuBEC 的增殖和迁移。DMC 对血管内皮生长因子和白细胞介素-8 的分泌没有明显影响，但抑制了肿瘤相关 EC 中内皮素-1 的分泌。DMC 处理小鼠的胶质瘤异种移植物导致肿瘤体积较小，微血管密度明显降低，与未处理的小鼠相比。体外和体内分析证实 DMC 具有抗血管生成活性。考虑到 DMC 既针对肿瘤细胞又针对肿瘤相关 EC，这种药物是一种很有前途的抗癌药物。
