ZFIN ID: ZDB-PUB-140724-4
An In Vivo Antilymphatic Screen in Zebrafish Identifies Novel Inhibitors of Mammalian Lymphangiogenesis and Lymphatic-Mediated Metastasis
Astin, J.W., Jamieson, S.M., Eng, T.C., Flores, M.V., Misa, J.P., Chien, A., Crosier, K.E., Crosier, P.S.
Date: 2014
Source: Molecular cancer therapeutics   13(10): 2450-62 (Journal)
Registered Authors: Chien, Annie, Crosier, Kathy, Crosier, Phil, Flores, Maria
Keywords: none
MeSH Terms:
  • Animals
  • Antineoplastic Agents/pharmacology*
  • Cinnarizine/pharmacology
  • Endothelial Cells/drug effects
  • Endothelial Cells/pathology
  • Female
  • Flunarizine/pharmacology
  • Humans
  • Isoxazoles/pharmacology
  • Kaempferols/pharmacology
  • Lymph Nodes/drug effects*
  • Lymph Nodes/pathology*
  • Lymphangiogenesis/drug effects*
  • Lymphatic Metastasis
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms/blood supply
  • Neoplasms/drug therapy*
  • Neoplasms/pathology
  • Random Allocation
  • Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
  • Zebrafish
PubMed: 25053822 Full text @ Mol. Cancer Ther.
ABSTRACT
The growth of new lymphatic vessels (lymphangiogenesis) in tumours is an integral step in the metastatic spread of tumour cells, first to the sentinel lymph nodes that surround the tumour and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use and there is an important potential clinical niche for anti-lymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have anti-lymphatic activity. These include kaempferol, a natural product found in plants, leflunomide, an inhibitor of pyrimidine biosynthesis, and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Anti-lymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumour-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model kaempferol administration was also associated with tumour deposits in the pancreas/diaphragm and flunarizine was found to be tumourigenic. While this screen revealed that zebrafish are a viable platform for the identification and development of mammalian anti-lymphatic compounds it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumour context.
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