Antiangiogenic Potential of Microbial Metabolite Elaiophylin for Targeting Tumor Angiogenesis.

Abstract

Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis assays. Elaiophylin dramatically suppressed in vitro angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF) at non-toxic concentrations. In addition, elaiophylin immensely inhibited in vivo angiogenesis of the chorioallantoic membrane (CAM) from growing chick embryos without cytotoxicity. The activation of VEGF receptor 2 (VEGFR2) in HUVECs by VEGF was inhibited by elaiophylin, resulting in the suppression of VEGF-induced activation of downstream signaling molecules, Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-κB (NFκB), matrix metalloproteinase (MMP)-2 and -9 which are closely associated with VEGF-induced angiogenesis. We also found that elaiophylin blocked tumor cell-induced angiogenesis both in vitro and in vivo. Elaiophylin downregulated the expression of VEGF by inhibiting hypoxia inducible factor-1α (HIF-1α) accumulation in tumor cells. To our knowledge, these results for the first time demonstrate that elaiophylin effectively inhibits angiogenesis and thus may be utilized as a new class of natural antiangiogenic agent for cancer therapy.

• Authors: Haet Nim Lim, Jun-Pil Jang, Jang Mi Han, Jae-Hyuk Jang, Jong Seog Ahn, Hye Jin Jung
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 3 (Mar 02 2018) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 29498688 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Anti-Infective Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Macrolides
• NF-kappa B
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• elaiophylin
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2
• Proto-Oncogene Proteins c-akt
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Angiogenesis Inhibitors (isolation & purification, pharmacology)
• Animals
• Anti-Infective Agents (isolation & purification, pharmacology)
• Biological Assay
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chick Embryo
• Chorioallantoic Membrane (blood supply, drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Macrolides (isolation & purification, pharmacology)
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• NF-kappa B (genetics, metabolism)
• Neovascularization, Pathologic (genetics, metabolism, pathology, prevention & control)
• Neuroglia
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Streptomyces (chemistry)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)