Mediators of Inflammation, 2016, 2016:1-17.

GEN-27, a Newly Synthetic Isoflavonoid, Inhibits the Proliferation of Colon Cancer Cells in Inflammation Microenvironment by Suppressing NF-KB Pathway

Yajing Wang, Ping Lu, Weifeng Zhang, et al

State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing 210009, China; Department of Organic Chemistry, China Pharmaceutical University, Jiangsu, Nanjing 210009, China

Nonresolving inflammation is one of the consistent features of the tumor microenvironment in the intestine and plays a critical role in the initiation and development of colon cancer. Here we reported the inhibitory effects of GEN-27, a new derivative of genistein, on the inflammation-related colon cancer cell proliferation and delineated the mechanism of its action. The results indicated that GEN-27 inhibited the proliferation of human colon tumor HCT116 cells stimulated by culture supernatants of LPS-induced human monocytes THP-1 cells and significantly decreased LPS-induced secretion of proinflammatory cytokines interleukin-6 and interleukin-1β in THP-1 cells. The HCT116 cell proliferation elicited by THP-1-conditioned medium could be blocked by the interleukin-1 receptor antagonist (IL-1RA). Further mechanistic study revealed that GEN-27 remarkably inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β in both HCT116 and THP-1 cells. In addition, GEN-27 markedly suppressed the HCT116 cell proliferation stimulated by IL-1β treatment, which was dependent on the inhibition of NF-κB/p65 nuclear localization, as verified by p65 overexpression and BAY 11-7082, an NF-κB inhibitor. Taken together, our findings established that GEN-27 modulated NF-κB signaling pathway involved in inflammation-induced cancer cells proliferation and therefore could be a potential chemopreventive agent against inflammation-associated colon cancer.

美国《炎症介质》，2016：1-17

GEN-27，一种新合成的异黄酮，通过抑制 NF -KB 途径抑制结肠癌细胞在炎症微环境中的增殖

王亚江，陆平，张伟峰等

国家重点实验室的天然药物、生理学、中国药科大学、江苏、南京210009年,中国;有机化学、中国药科大学,江苏,南京,210009年,中国

非分辨性炎症是肠中肿瘤微环境的一致特征之一，并在结肠癌的起始和发展中起关键作用。这里我们报道GEN-27的抑制效应,一个新的染料木黄酮的衍生物, 对炎症相关的结肠癌细胞增殖及其作用机制进行了界定。结果表明，GEN-27抑制LPS诱导的人单核细胞THP-1细胞的培养上清液刺激的人结肠肿瘤HCT 116细胞的增殖，并显着降低LPS诱导的促炎细胞因子白细胞介素-6和白细胞介素-1β在THP-1细胞。 THP-1条件培养基引起的HCT 116细胞增殖可被白细胞介素-1受体拮抗剂（IL-1RA）阻断。进一步的机械研究表明GEN-27显着抑制NF-κB的核易位和IκB和IKKα/β在HCT116和THP-1细胞中的磷酸化。此外，GEN-27显着抑制由IL-1β处理刺激的HCT 116细胞增殖，其取决于NF-κB/ p65核定位的抑制，如通过p65过表达和BAY 11-7082（NF-κB抑制剂）所证实的。综合起来，我们的研究结果确定GEN-27调节NF-κB信号通路参与炎症诱导的癌细胞增殖，因此可以是抗炎症相关结肠癌的潜在化学预防药物。