Institute of Anatomy, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany.
Investigating Institute of Molecular Biological System Transfer, Tehran 1417863171, Iran; Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, 141556453, Iran.
Biochem Pharmacol. 2015 Nov 1;98(1):51-68. doi: 10.1016/j.bcp.2015.08.105. Epub 2015 Aug 24.
5-Fluorouracil (5-FU), a common chemotherapeutic agent used for the treatment of colorectal cancer (CRC), by itself has inadequate response rates; highlighting the need for novel and improved treatment regimens for these patients. Resveratrol, a naturally-occurring polyphenol, has been linked with chemosensitizing potential and anticancer properties; however, the underlying mechanisms for these effects remain poorly understood. The effect of resveratrol in parental CRC cell lines (HCT116, SW480) and their corresponding isogenic 5-FU-chemoresistant derived clones (HCT116R, SW480R) was examined by MTT assays, intercellular junction formation and apoptosis by electron- and immunoelectron microscopy, nuclear factor-kappaB (NF-κB) and NF-κB regulated gene products by western blot analysis in a 3D-alginate microenvironment. Resveratrol blocked the proliferation of all four CRC cell lines and synergized the invasion inhibitory effects of 5-FU. Interestingly, resveratrol induced a transition from 5-FU-induced formation of microvilli to a planar cell surface, which was concomitant with up-regulation of desmosomes, gap- and tight junctions (claudin-2) and adhesion molecules (E-cadherin) expression in HCT116 and HCT116R cells. Further, resveratrol significantly attenuated drug resistance through inhibition of epithelial-mesenchymal transition (EMT) factors (decreased vimentin and slug, increased E-cadherin) and down-regulation of NF-κB activation and its translocation to the nucleus and abolished NF-κB-regulated gene end-products (MMP-9, caspase-3). Moreover, this suppression was mediated through inhibition of IκBα kinase and IκBα phosphorylation and degradation. Our results demonstrate that resveratrol can potentiate the anti-tumor effects of 5-FU on CRC cells by chemosensitizing them, inhibiting an EMT phenotype via up-regulation of intercellular junctions and by down-regulation of NF-κB pathway.
5-氟尿嘧啶（5-FU）是一种常用于治疗结直肠癌（CRC）的常用化疗药物，但本身的反应率不足；这突显了这些患者需要新的、改进的治疗方案。白藜芦醇是一种天然存在的多酚，与化疗增敏和抗癌特性有关；然而，这些作用的潜在机制仍知之甚少。通过 MTT 分析、电子和免疫电子显微镜下的细胞间连接形成和细胞凋亡、3D 藻酸盐微环境中的核因子-κB（NF-κB）和 NF-κB 调节基因产物的 Western blot 分析，研究了白藜芦醇对亲本 CRC 细胞系（HCT116、SW480）及其相应的 5-FU 化学抗性衍生克隆（HCT116R、SW480R）的影响。白藜芦醇阻断了所有四种 CRC 细胞系的增殖，并协同增强了 5-FU 的侵袭抑制作用。有趣的是，白藜芦醇诱导了从 5-FU 诱导的微绒毛形成到平面细胞表面的转变，这与桥粒、间隙和紧密连接（claudin-2）和粘附分子（E-钙粘蛋白）表达的上调同时发生在 HCT116 和 HCT116R 细胞中。此外，白藜芦醇通过抑制上皮-间充质转化（EMT）因子（减少波形蛋白和 slug，增加 E-钙粘蛋白）和下调 NF-κB 激活及其向核内易位以及消除 NF-κB 调节的基因终产物（MMP-9、caspase-3），显著减弱了耐药性。此外，这种抑制是通过抑制 IκBα 激酶和 IκBα 磷酸化和降解来介导的。我们的结果表明，白藜芦醇通过使 CRC 细胞对化疗增敏、通过上调细胞间连接抑制 EMT 表型以及通过下调 NF-κB 通路来增强 5-FU 对 CRC 细胞的抗肿瘤作用。
