3 5-bis (2 4-difluorobenzylidene)-4-piperidone a novel compound that affects pancreatic cancer growth and angiogenesis

摘要

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 Jagged1. In this study, we have 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 demonstrated that DiFiD induced G2/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 Jagged1, and two critical components of the γ-secretase enzyme complex Presenilin-1 and Nicastrin. Ectopic expression of the Notch Intracellular domain (NICD) rescued the cells from DiFiD-mediated growth suppression. DiFiD treated tumor xenografts also showed reduced levels of Jagged1, and the γ-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.