Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado at Denver and Health Sciences Center, Aurora, Colo 80045, USA.
J Thorac Cardiovasc Surg. 2011 Nov;142(5):1152-60. doi: 10.1016/j.jtcvs.2011.08.004.
Esophageal adenocarcinoma is an aggressive malignancy generally diagnosed after metastatic spread and currently lacks effective medical therapy. Expression of intracellular adhesion molecule-1 (ICAM-1) is an adverse prognostic indicator in various human tumor cells and contributes significantly to their metastatic potential. Statin therapy reduces circulating ICAM-1 levels in patients with coronary heart disease and is associated with reduction in progression from Barrett esophagus to esophageal adenocarcinoma. We hypothesize that statin therapy may attenuate growth and malignant potential via ICAM-1 expression and nuclear factor-kappa beta activation in human esophageal adenocarcinoma cells.
Verified human esophageal adenocarcinoma cells (FLO-1) were treated with simvastatin, atorvastatin, or pravastatin (10-, 30-, and 50-μmol/L concentrations). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide viability, 5-bromo-2'-deoxyuridine proliferation, or annexin V apoptosis assays were performed, or cells were stimulated with tumor necrosis factor-alpha and collected for immunoblotting and flow cytometry.
Simvastatin decreased cell viability and proliferation while increasing apoptosis in a dose-dependent manner (P < .05). Simvastatin attenuated total cellular and cell-surface ICAM-1 expression as well as nuclear factor-kappa beta activation (P < .05). Atorvastatin had mild effects and pravastatin had essentially no effect on growth and metastatic potential of these cells.
We demonstrate that treatment of human esophageal adenocarcinoma cells with simvastatin attenuates growth, by decreasing cell viability, decreasing cell proliferation, and increasing apoptosis, and attenuates metastatic potential, by decreasing expression of key metastatic markers. These findings identify simvastatin as a potential therapeutic and chemopreventive modality to thwart the progression of esophageal adenocarcinoma.
食管腺癌是一种侵袭性恶性肿瘤，通常在转移扩散后才被诊断出来，目前缺乏有效的医学治疗方法。细胞间黏附分子-1（ICAM-1）的表达是各种人类肿瘤细胞的不良预后指标，并且对其转移潜能有重要贡献。他汀类药物治疗可降低冠心病患者的循环 ICAM-1 水平，并与降低巴雷特食管向食管腺癌的进展相关。我们假设他汀类药物治疗可能通过抑制 ICAM-1 表达和核因子-κB 激活来减弱人食管腺癌细胞的生长和恶性潜能。
用辛伐他汀、阿托伐他汀或普伐他汀（10-、30-和 50-μmol/L 浓度）处理经验证的人食管腺癌细胞（FLO-1）。进行 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）活力、5-溴-2'-脱氧尿苷增殖或 Annexin V 凋亡测定，或用肿瘤坏死因子-α刺激细胞并进行免疫印迹和流式细胞术分析。
辛伐他汀以剂量依赖性方式降低细胞活力和增殖，同时增加细胞凋亡（P <.05）。辛伐他汀减弱了总细胞和细胞表面 ICAM-1 的表达以及核因子-κB 的激活（P <.05）。阿托伐他汀的作用轻微，普伐他汀对这些细胞的生长和转移潜能基本没有影响。
我们证明用辛伐他汀治疗人食管腺癌细胞可通过降低细胞活力、降低细胞增殖和增加凋亡来减弱生长，并通过降低关键转移标志物的表达来减弱转移潜能。这些发现表明辛伐他汀可能是一种潜在的治疗和化学预防方法，可阻止食管腺癌的进展。
