姜黄素和来自 Wiko stroemia indica 的新二氢黄酮 wikstroflavone B 通过阻断 FAK/STAT3 信号通路协同抑制鼻咽癌细胞的增殖和转移。
Curcumin and wikstroflavone B, a new biflavonoid isolated from Wikstroemia indica, synergistically suppress the proliferation and metastasis of nasopharyngeal carcinoma cells via blocking FAK/STAT3 signaling pathway.
机构信息
Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, 510515 Guangzhou, China.
The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, 510515 Guangzhou, China.
出版信息
Phytomedicine. 2020 Dec;79:153341. doi: 10.1016/j.phymed.2020.153341. Epub 2020 Sep 19.
BACKGROUND
Curcumin (CUR) is a natural diarylheptanoid with marked anti-tumor activities. Recent investigations demonstrate that CUR combines with some other phytochemicals exerts advantages over its single application manifested as lower toxicity, higher efficacy or more significant reversal of multidrug resistance.
PURPOSE
This study aimed to elucidate a new biflavonoid (wikstroflavone B, WFB) isolated from Wikstroemia indica and to assess the synergistic inhibition of combined CUR and WFB (CUR/WFB) on human nasopharyngeal carcinoma (NPC) cell lines proliferation and metastasis.
METHODS
WFB was obtained through sequential chromatographic methods including silica gel, Sephadex LH-20 and preparative HPLC. Its structure was determined by HRESIMS, 1D and 2D NMR spectroscopic analysis. The absolute configuration of WFB was assigned through comparison of experimental and calculated optical rotation (OR) values. Changes in cellular viability, migration and invasion were assessed by MTT, colony formation, wound healing and Transwell assays. The nature of synergistic interaction of CUR/WFB was determined through the combination index (CI) method under the median-effect analysis. Expression levels of indicated mRNAs and proteins were measured by qRT-PCR and Western blotting assays, respectively.
RESULTS
WFB was isolated and structural elucidated. Compared with CUR or WFB used alone, CUR/WFB treatment inhibited more effectively on the cell viability, colony formation, cell migration and invasion. Both CI and dose reduction index (DRI) values indicated the significant synergistic effects existed between CUR and WFB. Besides, CUR/WFB showed the marked modulation on the genes involved in cell proliferation (survivin, cyclin D1, p53 and p21) and metastasis (MMP-2, MMP-9 and FAK). CUR/WFB treatment was also found to restrain the phosphorylation of FAK and STAT3 proteins. When pretreatment with a FAK inhibitor, the cell viability and metastasis were significantly attenuated.
CONCLUSION
The results indicate that WFB can synergistically increase the inhibitory effects of CUR on NPC cells proliferation and metastasis, and these findings may afford a rational approach for developing the antitumor medications.
背景
姜黄素（CUR）是一种天然二芳基庚烷类化合物，具有显著的抗肿瘤活性。最近的研究表明，CUR 与其他一些植物化学物质结合使用比单独应用具有优势，表现为毒性更低、疗效更高或对多药耐药性的逆转更显著。
目的
本研究旨在阐明从密花树中分离得到的一种新的双黄酮（密花黄素 B，WFB），并评估 CUR 和 WFB（CUR/WFB）联合抑制人鼻咽癌（NPC）细胞系增殖和转移的协同作用。
方法
通过硅胶、Sephadex LH-20 和制备型 HPLC 等顺序色谱方法获得 WFB。通过高分辨率电喷雾质谱（HRESIMS）、一维和二维 NMR 光谱分析确定其结构。通过比较实验和计算的旋光（OR）值来确定 WFB 的绝对构型。通过 MTT、集落形成、划痕愈合和 Transwell 测定评估细胞活力、迁移和侵袭的变化。通过中效分析的组合指数（CI）方法确定 CUR/WFB 的协同作用性质。通过 qRT-PCR 和 Western blot 测定分别测量指示 mRNA 和蛋白质的表达水平。
结果
WFB 被分离并结构阐明。与 CUR 或 WFB 单独使用相比，CUR/WFB 处理更有效地抑制细胞活力、集落形成、细胞迁移和侵袭。CI 和剂量减少指数（DRI）值均表明 CUR 和 WFB 之间存在显著的协同作用。此外，CUR/WFB 对参与细胞增殖（survivin、cyclin D1、p53 和 p21）和转移（MMP-2、MMP-9 和 FAK）的基因有明显的调节作用。CUR/WFB 处理还发现能抑制 FAK 和 STAT3 蛋白的磷酸化。当用 FAK 抑制剂预处理时，细胞活力和转移明显减弱。
结论
结果表明，WFB 可以协同增强 CUR 对 NPC 细胞增殖和转移的抑制作用，这些发现可能为开发抗肿瘤药物提供合理的方法。
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