Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.
Cancer Sci. 2022 Dec;113(12):4374-4384. doi: 10.1111/cas.15576. Epub 2022 Sep 20.
Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to Apc mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.
尽管已经有许多关于结直肠肿瘤的化学预防研究报告，但目前尚无有效和安全的预防剂。我们通过使用连接图谱（CMAP）分析结合结直肠腺瘤（CRA）患者来源的类器官（PDO）的体外筛选，从美国食品和药物管理局（FDA）批准的化合物中全面寻找针对结直肠肿瘤的候选预防化合物。我们基于 CRA 和正常上皮标本的 DNA 微阵列分析生成了 CRA 特异性基因特征，将其应用于 1309 种 FDA 批准的化合物的 CMAP 分析，并鉴定出 121 种可能消除基因特征的候选化合物。我们将它们缩小到 15 种化合物，并评估了它们在体外抑制 CRA-PDO 生长的作用。最后，我们确定白藜芦醇（一种多酚类植物化学物质）是一种与正常上皮 PDO 相比对 CRA-PDO 生长具有最强抑制作用的化合物。当白藜芦醇以 15 或 30mg/kg 的剂量给予 Apc 小鼠时，与对照组小鼠相比，两组小鼠的息肉（腺瘤）数量均显著减少。同样，与对照组大鼠相比，用 10 或 100mg/白藜芦醇处理的氧化偶氮甲烷注射大鼠的息肉（腺瘤）数量也显著减少。用白藜芦醇处理的大鼠腺瘤的微阵列分析显示，Wnt 信号通路中的关键分子 LEF1 的表达变化（下调）最大。白藜芦醇处理显著下调了 CRA-PDO 中的 Wnt 靶基因（MYC）。我们的数据表明，白藜芦醇可能是预防结直肠肿瘤的最有效化合物，其功效是通过抑制 Wnt 信号通路中的 LEF1 表达介导的。
