Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Vet. Res. Bldg. 410, College Station, TX 77843, USA.
Mol Cancer Res. 2011 Feb;9(2):195-202. doi: 10.1158/1541-7786.MCR-10-0363. Epub 2010 Dec 14.
Ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094) is a novel nitric oxide (NO) chimera containing an nonsteroidal anti-inflammatory drug (NSAID) and NO moieties and also a disulfide pharmacophore that in itself exhibits cancer chemopreventive activity. In this study, the effects and mechanism of action of GT-094 were investigated in RKO and SW480 colon cancer cells. GT-094 inhibited cell proliferation and induced apoptosis in both cell lines and this was accompanied by decreased mitochondrial membrane potential (MMP) and induction of reactive oxygen species (ROS), and these responses were reversed after cotreatment with the antioxidant glutathione. GT-094 also downregulated genes associated with cell growth [cyclin D1, hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR)], survival (bcl-2, survivin), and angiogenesis [VEGF and its receptors (VEGFR1 and VEGFR2)]. Results of previous RNA interference studies in this laboratory has shown that these genes are regulated, in part, by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in colon and other cancer cell lines and not surprisingly, GT-094 also decreased Sp1, Sp3, and Sp4 in colon cancer cells. GT-094-mediated repression of Sp and Sp-regulated gene products was due to downregulation of microRNA-27a (miR-27a) and induction of ZBTB10, an Sp repressor that is regulated by miR-27a in colon cancer cells. Moreover, the effects of GT-094 on Sp1, Sp3, Sp4, miR-27a, and ZBTB10 were also inhibited by glutathione suggesting that the anticancer activity of GT-094 in colon cancer cells is due, in part, to activation of an ROS-miR-27a:ZBTB10-Sp transcription factor pathway.
2-((2,3-二(硝氧基)丙基)二硫基)苯甲酸乙酯（GT-094）是一种新型的一氧化氮（NO）杂合体，含有非甾体抗炎药（NSAID）和 NO 部分，以及本身具有抗癌化学预防活性的二硫键药效团。在这项研究中，研究了 GT-094 在 RKO 和 SW480 结肠癌细胞中的作用和作用机制。GT-094 抑制了这两种细胞系的细胞增殖并诱导了细胞凋亡，这伴随着线粒体膜电位（MMP）的降低和活性氧（ROS）的诱导，这些反应在用抗氧化剂谷胱甘肽进行共处理后得到逆转。GT-094 还下调了与细胞生长[细胞周期蛋白 D1、肝细胞生长因子受体（c-Met）、表皮生长因子受体（EGFR）]、存活（bcl-2、survivin）和血管生成[血管内皮生长因子（VEGF）及其受体（VEGFR1 和 VEGFR2）]相关的基因。本实验室之前的 RNA 干扰研究结果表明，这些基因部分受到特异性蛋白（Sp）转录因子 Sp1、Sp3 和 Sp4 的调节，这些转录因子在结肠和其他癌细胞系中过度表达，因此毫不奇怪，GT-094 也降低了结肠癌细胞中的 Sp1、Sp3 和 Sp4。GT-094 介导的 Sp 抑制和 Sp 调节的基因产物的抑制归因于 microRNA-27a（miR-27a）的下调和 ZBTB10 的诱导，ZBTB10 是一种 Sp 抑制剂，在结肠癌细胞中受 miR-27a 调节。此外，GT-094 对 Sp1、Sp3、Sp4、miR-27a 和 ZBTB10 的作用也被谷胱甘肽抑制，这表明 GT-094 在结肠癌细胞中的抗癌活性部分归因于活性氧-miR-27a：ZBTB10-Sp 转录因子途径的激活。
