Anti-Angiogenic Properties of BDDPM, a Bromophenol from Marine Red Alga Rhodomela confervoides, with Multi Receptor Tyrosine Kinase Inhibition Effects

• Published in: International journal of molecular sciences 2015-06, Vol.16 (6), p.13548-13560
• Main Authors: Wang, Shuaiyu, Wang, Li-Jun, Jiang, Bo, Wu, Ning, Li, Xiangqian, Liu, Shaofang, Luo, Jiao, Shi, Dayong
• Format: Article
• Language: English
• Subjects: Algae; Angiogenesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; anti-angiogenesis; bromophenol; eNOS; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hydrocarbons, Brominated - chemistry; Hydrocarbons, Brominated - pharmacology; Kinases; multi-target inhibitor; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Phenols; PKB/Akt; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Fibroblast Growth Factor, Type 2 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Rhodomela confervoides; Rhodomelaceae; Rhodophyta - chemistry; RTKs; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms160613548

Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a bromophenol first isolated from Rhodomelaceae confervoides. Our previous studies showed that BDDPM exerts PTP1B-inhibiting activity and anti-cancer activity against a wide range of tumor cells while it also showed lower cytotoxicity against normal cells. In the present study, we found that BDDPM exhibits significant activities toward angiogenesis in vitro. BDDPM inhibits multiple angiogenesis processes, including endothelial cell sprouting, migration, proliferation, and tube formation. Further kinase assays investigations found that BDDPM is a potent selective, but multi-target, receptor tyrosine kinase (RTKs) inhibitor. BDDPM (10 μM) inhibits the activities of fibroblast growth factor receptor 2 and 3 (FGFR2, 3), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor α (PDGFRα) (inhibition rate: 57.7%, 78.6%, 78.5% and 71.1%, respectively). Moreover, BDDPM also decreases the phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS), as well as nitric oxide (NO) production in a dose dependent manner. These results indicate that BDDPM can be exploited as an anti-angiogenic drug, or as a lead compound for the development of novel multi-target RTKs inhibitors.