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

Shuaiyu Wang,Shaofang Liu,Jiao Luo,Xiangqian Li,Dayong Shi,Li-Jun Wang,Bo Jiang,Ning Wu

doi:10.3390/ijms160613548

Abstract

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.

Highlights

Tumor and tumor blood vessels are two major targets in exploiting anti-cancer drugs [1]
BDDPM (10 μM) potently inhibits the receptor tyrosine kinase (RTKs) activities of recombinant FGFR2, FGFR3, vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor α (PDGFRα) in vitro (Results showing an inhibition higher than 50% are considered to represent significant effects of the test compounds), while displays weak activity against EGFR, FGFR1, PDGFRβ and FGFR4
These results demonstrated that BDDPM is a multi-target inhibitor of FGFR2, FGFR3, VEGFR2 and PDGFRα

Summary

Introduction

Tumor and tumor blood vessels are two major targets in exploiting anti-cancer drugs [1]. More and more cancer patients have benefitted from these two targeted therapeutics, some of the therapeutics are target oncogenic pathways in cancer cells, others are target angiogenic pathways in blood vessels, or both [2]. A rising trend in research demonstrates that drugs that can block more than one molecular target or pathway at the same time can cure cancer more efficiently [3]. Several studies have reported that BDDPM exerts anti-bacterial and feeding-deterrent effects [4,5,6]. Our recent study found that BDDPM exerts anti-cancer activity against several cancer cell lines while it has less cytotoxic activity on human umbilical vein endothelial cells (HUVECs) [8]. The anti-angiogenic effect of BDDPM has not been reported. We investigated the effects of BDDPM on angiogenesis and the potential mechanisms in vitro

Results

Discussion

Conclusion