title: 3,5-bis(2,4-difluorobenzylidene)-4-piperidone, a novel compound that affects pancreatic cancer growth and angiogenesis.
abstract: 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 γ-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 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.
authors: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA. dsubramaniam@kumc.edu
authors: Dharmalingam
authors: D
authors: Subramaniam
authors: Nathan D
authors: ND
authors: Nicholes
authors: Animesh
authors: A
authors: Dhar
authors: Shahid
authors: S
authors: Umar
authors: Vibhudutta
authors: V
authors: Awasthi
authors: Danny R
authors: DR
authors: Welch
authors: Roy A
authors: RA
authors: Jensen
authors: Shrikant
authors: S
authors: Anant
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001597:Benzylidene Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010881:Piperidones / Q000494:pharmacology* / Q000627:therapeutic use; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C570661:3,5-bis(2,4-difluorobenzylidene)-4-piperidone; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D018797:Cell Cycle Proteins; D010881:Piperidones; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases