A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells.
A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells.
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一种新型查耳酮衍生物 S17 通过 ROS 依赖性 DR5 上调诱导胃癌细胞凋亡
DOI：
10.1038/s41598-017-10400-3
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发表时间：
2017-08-29
影响因子：
4.6
通讯作者：
Jin CY
中科院分区：
文献类型：
--
作者：
Zhang S;Li T;Zhang L;Wang X;Dong H;Li L;Fu D;Li Y;Zi X;Liu HM;Zhang Y;Xu H;Jin CY
通过Willimison醚化反应和Claisen-Schmidt缩合反应，设计并合成了一系列醚化查尔酮衍生物。其中化合物2-c（化学名为S17）通过对5种胃癌细胞（EC 109、HepG 2、MCF 7、MG 803、SKNSH）的生长抑制作用的研究，筛选出对胃癌细胞（MG 803）的抑制作用最强的化合物。S17对胃癌细胞HGC 27和胃癌细胞SGC 7901的增殖抑制作用较强，但对非恶性胃上皮细胞GES 1的细胞毒性较小。S17通过调节Bcl-2家族蛋白和激活caspase 9/3级联反应，有效杀伤胃癌细胞。S17还上调DR 5表达，DR 5敲低部分逆转了S17诱导的细胞凋亡、caspase激活和MMP降低。S17可诱导MGC 803细胞产生活性氧，并激活Keap/Nrf 2通路，活性氧清除剂N-乙酰半胱氨酸（NAC）可完全阻断S17的这种作用。腹腔注射S17可显著抑制MGC 803细胞在异种移植小鼠模型中的体内生长，而未观察到毒性。这些结果表明，S17是一种铅溴化查尔酮衍生物，值得进一步研究用于预防和治疗胃癌。
A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.
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DOI：
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发表时间：
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期刊：
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