An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation
An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation
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异恶唑衍生物 SHU00238 通过 miRNA 调节抑制结直肠癌生长
DOI：
10.3390/molecules24122335
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发表时间：
2019
期刊：
影响因子：
4.6
通讯作者：
Liang Yajun
中科院分区：
文献类型：
--
作者：
Wang Haoyu;Ma Yurui;Lin Yifan;Liu Jiajie;Chen Rui;Xu Bin;Liang Yajun
结直肠癌（CRC）是全世界癌症相关死亡的主要原因。异恶唑啉及其衍生物是一类重要的五元杂环化合物，在药物开发中起着重要的作用。在我们以前的研究中，我们用一种有效的方法合成了一系列异恶唑衍生物。在这项研究中，我们评估了它们对肿瘤细胞生长的影响。用异恶唑衍生物处理HCT 116细胞;使用八肽胆囊收缩素（CCK-8）测定来计算每种衍生物的IC 50（半数最大抑制浓度）。化合物SHU 00238是通过硝酸铜介导的烯属吖内酯与萘-1，4-二酮的[2+2+1]环加成反应获得的，具有较低的IC 50;我们在进一步的试验中分析了其抑制活性。流式细胞术检测细胞凋亡; SHU 00238注射液用于治疗荷瘤小鼠。我们发现SHU 00238在体外抑制细胞活力并促进细胞凋亡。SHU 00238处理显著抑制体内结肠肿瘤生长。此外，我们还比较了SHU 00238处理前后HCT 116细胞中miRNAs表达的变化。miRNA谱显示SHU 00238处理通过调节一组miRNA影响细胞命运。结论SHU 00238通过miRNA调控抑制CRC肿瘤细胞增殖并促进细胞凋亡。
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.