多甲氧基黄酮靶向癌症干性并增强 5-氟尿嘧啶在结直肠癌细胞 3D 模型中的抗增殖作用。
Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer.
机构信息
iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
出版信息
Nutrients. 2019 Feb 2;11(2):326. doi: 10.3390/nu11020326.
Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of , , , and genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers and were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of and . Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing and reducing and ) and nobiletin was capable of downregulating and expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.
柑橘类水果中的多甲氧基黄酮（PMFs）被报道具有抗癌潜力。然而，关于它们对癌症干细胞（CSC）群体的影响的信息却很缺乏，因为CSC 被认为是肿瘤起始、复发和化疗耐药的原因。在这项研究中，我们使用在搅拌条件下培养了 7 天的 HT29 细胞球体组成的结直肠癌细胞 3D 模型，评估了橙皮提取物（OPE）及其主要 PMFs，即诺必灵、橙皮素、川陈皮素和蒙花苷四甲醚对细胞增殖和干细胞特性的影响。然后，通过软琼脂试验、ALDH1 活性和特定生物标志物的相对定量基因表达分析，对 HT29 细胞球体的干细胞特性、自我更新和间充质特征进行了表征。然后，评估了 OPE 和 PMFs 对减少细胞增殖和调节癌症干细胞特性和自我更新的影响。结果表明，与单层培养相比，HT29 细胞球体具有更高的 ALDH1 活性（81.97%±5.27%比 2D 中的 63.55%±17.49%），上调了 、 、 、 基因（1.83±0.34、2.54±0.51、2.03±0.15 和 6.12±1.59 倍）和具有高自我更新能力（352±55 个集落，而 2D 中为 253±42 个集落）。用 OPE（1mg/mL）孵育显著抑制了细胞增殖并调节了癌症干细胞特性和自我更新能力：集落形成、ALDH1 活性和癌症干细胞标志物 和 的表达显著降低（分别为 0.66±0.15 和 0.51±0.14 倍）。在所有 PMFs 中，橙皮素通过减少集落形成和 、 的表达，对 CSC 群体的靶向作用最为有效。蒙花苷四甲醚被证明可以调节间充质/转移转化的标志物（增加 和减少 和 ），诺必灵能够下调 和 的表达。重要的是，所有 PMFs 和 OPE 均与 5-氟尿嘧啶协同作用，改善了该药物的抗增殖反应。
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