Departments of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, BK21 Project, Chonbuk National University, Jeonju, Republic of Korea.
Eur J Cancer Prev. 2011 Mar;20(2):102-11. doi: 10.1097/CEJ.0b013e328341e38f.
Earlier studies have shown that tolfenamic acid (Tol) exhibits anticancer activity in several cancer models by inhibiting tumor growth and angiogenesis. However, the chemopreventive effect of Tol on a cervical cancer model and the underlying mechanism of action are unknown. In this study, Tol was found to inhibit cell proliferation by inducing apoptosis without affecting cyclo-oxygenase 2 expression, but ampiroxicam did not. Tol decreases the specificity protein 1 (Sp1) mRNA and its promoter activity in KB cervical cancer cells, and the downregulation of Sp1 protein by affecting several proteins that contain GC-rich sites on their promoters. Studies using small interference RNA and an Sp1-specific inhibitor (mithramycin A) confirmed that the decrease in Sp1 by Tol affects survivin and p27. Tol also inhibited tumor growth and Sp1 protein in athymic nude mice xenografts. These results show that Tol could be a potent anticervical cancer drug that acts by regulating Sp1 protein and its downstream pathways.
早期研究表明，托芬那酸（Tol）通过抑制肿瘤生长和血管生成，在几种癌症模型中表现出抗癌活性。然而，Tol 对宫颈癌模型的化学预防作用及其作用机制尚不清楚。本研究发现，Tol 通过诱导细胞凋亡而不影响环氧化酶 2 的表达来抑制细胞增殖，但氨比西林则没有。Tol 降低 KB 宫颈癌细胞中的特异性蛋白 1（Sp1）mRNA 及其启动子活性，通过影响启动子上含有富含 GC 位点的几种蛋白来下调 Sp1 蛋白。使用小干扰 RNA 和 Sp1 特异性抑制剂（mithramycin A）的研究证实，Tol 对 Sp1 的下调影响了 survivin 和 p27。Tol 还抑制了裸鼠异种移植瘤的肿瘤生长和 Sp1 蛋白。这些结果表明，Tol 可能是一种有效的抗宫颈癌药物，通过调节 Sp1 蛋白及其下游途径发挥作用。
