Papineni Sabitha, Chintharlapalli Sudhakar, Abdelrahim Maen, Lee Syng-ook, Burghardt Robert, Abudayyeh Ala, Baker Cheryl, Herrera Luis, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
Carcinogenesis. 2009 Jul;30(7):1193-201. doi: 10.1093/carcin/bgp092. Epub 2009 Apr 30.
The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
非甾体抗炎药托芬那酸（TA）抑制SEG-1和BIC-1食管癌细胞的增殖，其半数最大生长抑制浓度值分别为36和48μM。TA还增加了两种细胞系中膜联蛋白V的染色，表明其具有促凋亡活性。用TA处理SEG-1和BIC-1细胞长达72小时可降低特异性蛋白（Sp）转录因子Sp1、Sp3和Sp4的表达，同时伴随着特征明确的Sp调节基因细胞周期蛋白D1、血管内皮生长因子和生存素表达的降低。TA还降低了肝细胞生长因子受体（c-Met），这是一种受体酪氨酸激酶，在食管癌细胞和肿瘤中过表达，是一个重要的药物靶点。在SEG-1和BIC-1细胞中通过RNA干扰敲低Sp1、Sp3和Sp4也降低了c-Met的表达，表明c-Met是食管癌细胞中的一个Sp调节基因。Sp1在食管癌细胞和肿瘤中过表达，在患者的食管肿瘤中观察到Sp1染色增加。TA（20mg/kg/天）还可降低携带SEG-1细胞异种移植的无胸腺裸鼠的肿瘤生长和重量，同时伴随着处理小鼠肿瘤中凋亡增加以及Sp1和c-Met染色减少。因此，TA依赖的Sp转录因子和c-Met的下调定义了一种治疗食管癌的新型化疗方法。
