The anti-angiogenic and anti-tumor activity of synthetic phenylpropenone derivatives is mediated through the inhibition of receptor tyrosine kinases.
Abnormal angiogenesis plays a critical role in the pathogenesis of various diseases such as cancer and chronic inflammation. A variety of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), exert their action through endothelial receptor tyrosine kinases (RTKs). The synthetic phenylpropenone derivatives, used in this study were the following: 1,3-diphenyl-propenone (DPhP), 3-phenyl-1-thiophen-2-yl-propenone (PhT2P), 3-phenyl-1-thiophen-3-yl-propenone (PhT3P) and 1-furan-2-yl-3-phenyl-propenone (FPhP). These derivatives were screened for their inhibitory effect on VEGF-induced angiogenesis in vitro using HUVECs and in vivo using chick chorioallantoic membrane (CAM). The order of anti-angiogenic activity was DPhP>FPhP>PhT3P>PhT2P. The most effective compound DPhP, also known as chalcone, showed weak VEGF receptor tyrosine kinase activity compared with the specific inhibitor, SU4312 (3-[[4-(dimethylamino)phenyl]methylene]-1,3-dihydro-2H-indol-2-one). However, DPhP also inhibited several other receptor tyrosine kinases including Tie-2, epithermal growth factor (EGF) receptor, EphB2, fibroblast growth factor (FGF) receptor 3 and insulin-like growth factor-1 (IGF-1) receptor, as revealed by a receptor tyrosine kinase array assay. In addition, the down-stream signaling, including ERK phosphorylation and NF-κB activation, after receptor activation was significantly inhibited by DPhP. Furthermore, in the HT29 human colon cancer cell-inoculated CAM assay, the tumor growth and tumor-induced angiogenesis was significantly inhibited by DPhP (10μg/ml). These results suggest that the simple flavonoid, DPhP (chalcone), has valuable potential as an antiangiogenic and anti-cancer agent, and its action is mediated through the inhibition of multi-target RTKs including VEGF receptor 2.
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Jong-Suk
JS
Lee
Youra
Y
Kang
Jong Tae
JT
Kim
Dinesh
D
Thapa
Eung-Seok
ES
Lee
Jung-Ae
JA
Kim
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011427:Propiophenones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D011427:Propiophenones; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D020794:Receptor Protein-Tyrosine Kinases