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首页> 外文期刊>Molecular cancer therapeutics >3,5-bis(2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis.
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3,5-bis(2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis.

机译：3,5-双（2,4-二氟亚苄基）-4-哌啶酮，一种影响胰腺癌生长和血管生成的新型化合物。

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Dysregulated Notch signaling plays an important role in the progression of cancer. Notch signaling affects tumor growth and angiogenesis through the actions of its ligand Jagged-1. In this study, we developed a novel compound 3,5-bis(2,4-difluorobenzylidene)-4-piperidone (DiFiD) and determined that it inhibits cancer cell growth and its effects on Notch signaling. Intraperitoneal administration of DiFiD significantly suppressed growth of pancreatic cancer tumor xenografts. There was a reduction in CD31-positive blood vessels, suggesting that there was an effect on angiogenesis. In vitro, DiFiD inhibited the proliferation of various human and mouse pancreatic cancer cells while increasing activated caspase-3. Cell-cycle analyses showed that DiFiD induced G(2)-M arrest and decreased the expression of cell-cycle-related proteins cyclin A1 and D1 while upregulating cyclin-dependent kinase inhibitor p21WAF1. We next determined the mechanism of action. DiFiD reduced Notch-1 activation, resulting in reduced expression of its downstream target protein Hes-1. We further determined that the reduced Notch-1 activation was due to reduction in the ligand Jagged-1 and two critical components of the gamma-secretase enzyme complex presenilin-1 and nicastrin. Ectopic expression of the Notch intracellular domain rescued the cells from DiFiD-mediated growth suppression. DiFiD-treated tumor xenografts also showed reduced levels of Jagged-1 and the gamma-secretase complex proteins presenilin-1 and nicastrin. Taken together, these data suggest that DiFiD is a novel potent therapeutic agent that can target different aspects of the Notch signaling pathway to inhibit both tumor growth and angiogenesis.
机译：Notch信号转导失调在癌症进展中起重要作用。 Notch信号通过其配体Jagged-1的作用影响肿瘤的生长和血管生成。在这项研究中，我们开发了一种新型化合物3,5-双（2,4-二氟亚苄基）-4-哌啶酮（DiFiD），并确定它抑制癌细胞的生长及其对Notch信号的影响。 DiFiD的腹膜内给药显着抑制了胰腺癌肿瘤异种移植物的生长。 CD31阳性血管减少，表明对血管生成有影响。在体外，DiFiD抑制了各种人类和小鼠胰腺癌细胞的增殖，同时增加了活化的caspase-3。细胞周期分析表明，DiFiD诱导G（2）-M逮捕并减少细胞周期相关蛋白细胞周期蛋白A1和D1的表达，同时上调细胞周期蛋白依赖性激酶抑制剂p21WAF1。接下来，我们确定了作用机理。 DiFiD减少了Notch-1的激活，导致其下游靶蛋白Hes-1的表达降低。我们进一步确定，Notch-1激活的减少是由于配体Jagged-1和γ-分泌酶复合物presenilin-1和nicastrin的两个关键成分减少所致。 Notch细胞内域的异位表达使细胞免受DiFiD介导的生长抑制。 DiFiD处理的肿瘤异种移植物还显示出降低的Jagged-1和γ-分泌酶复合蛋白presenilin-1和nicastrin的水平。综上，这些数据表明DiFiD是一种新型的强效治疗剂，可以靶向Notch信号通路的不同方面，以抑制肿瘤的生长和血管生成。

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